6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors

ABSTRACT

Compounds of the formula 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , and Q 1  are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of hyperproliferative diseases such as cancer, inflammation, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system.

This application claims the benefit of U.S. Application No. 60/559,250filed 2 Apr. 2004.

BACKGROUND OF THE INVENTION

The present invention is directed to novel heterobicyclic compounds,their salts, and compositions comprising them. In particular, thepresent invention is directed to novel heterobicyclic compounds thatinhibit the activity of tyrosine kinase enzymes in animals, includinghumans, for the treatment and/or prevention of various diseases andconditions such as cancer.

Protein tyrosine kinases (PTKs) are enzymes that catalyse thephosphorylation of specific tyrosine residues in various cellularproteins involved in regulation of cell proliferation, activation, ordifferentiation (Schlessinger and Ulrich, 1992, Neuron 9:383-391).Aberrant, excessive, or uncontrolled PTK activity has been shown toresult in uncontrolled cell growth and has been observed in diseasessuch as benign and malignant proliferative disorders, as well as havingbeen observed in diseases resulting from an inappropriate activation ofthe immune system (e.g., autoimmune disorders), allograft rejection, andgraft vs. host disease. In addition, endothelial-cell specific receptorPTKs such as KDR and Tie-2 mediate the angiogenic process, and are thusinvolved in supporting the progression of cancers and other diseasesinvolving inappropriate vascularization (e.g., diabetic retinopathy,choroidal neovascularization due to age-related macular degeneration,psoriasis, arthritis, retinopathy of prematurity, infantilehemangiomas).

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular). The Receptor Tyrosine Kinases (RTKs) comprise alarge family of transmembrane receptors with at least nineteen distinctRTK subfamilies having diverse biological activities. The RTK familyincludes receptors that are crucial for the growth and differentiationof a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem.57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990). Theintrinsic function of RTKs is activated upon ligand binding, whichresults in phosphorylation of the receptor and multiple cellularsubstrates, and subsequently results in a variety of cellular responses(Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, RTK mediatedsignal transduction is initiated by extracellular interaction with aspecific growth factor (ligand), typically followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity and receptor trans-phosphorylation. Binding sites are therebycreated for intracellular signal transduction molecules and lead to theformation of complexes with a spectrum of cytoplasmic signalingmolecules that facilitate a corresponding cellular response such as celldivision, differentiation, metabolic effects, and changes in theextracellular microenvironment (Schlessinger and Ullrich, 1992, Neuron9:1-20).

Malignant cells are associated with the loss of control over one or morecell cycle elements. These elements range from cell surface receptors tothe regulators of transcription and translation, including theinsulin-like growth factors, insulin growth factor-I (IGF-1) and insulingrowth factor-2 (IGF-2) (M. J. Ellis, “The Insulin-Like Growth FactorNetwork and Breast Cancer”, Breast Cancer, Molecular Genetics,Pathogenesis and Therapeutics, Humana Press 1999). The insulin growthfactor system consists of families of ligands, insulin growth factorbinding proteins, and receptors.

A major physiological role of the IGF-1 system is the promotion ofnormal growth and regeneration. Overexpressed IGF-1R (type 1insulin-like growth factor receptor) can initiate mitogenesis andpromote ligand-dependent neoplastic transformation. Furthermore, IGF-1Rplays an important role in the establishment and maintenance of themalignant phenotype.

IGF-1R exists as a heterodimer, with several disulfide bridges. Thetyrosine kinase catalytic site and the ATP binding site are located onthe cytoplasmic portion of the beta subunit. Unlike the epidermal growthfactor (EGF) receptor, no mutant oncogenic forms of the IGF-1R have beenidentified. However, several oncogenes have been demonstrated to affectIGF-1 and IGF-1R expression. The correlation between a reduction ofIGF-1R expression and resistance to transformation has been seen.Exposure of cells to the mRNA antisense to IGF-1R RNA prevents soft agargrowth of several human tumor cell lines.

Apoptosis is a ubiquitous physiological process used to eliminatedamaged or unwanted cells in multicellular organisms. Misregulation ofapoptosis is believed to be involved in the pathogenesis of many humandiseases. The failure of apoptotic cell death has been implicated invarious cancers, as well as autoimmune disorders. Conversely, increasedapoptosis is associated with a variety of diseases involving cell losssuch as neurodegenerative disorders and AIDS. As such, regulators ofapoptosis have become an important therapeutic target. It is nowestablished that a major mode of tumor survival is escape fromapoptosis. IGF-1R abrogates progression into apoptosis, both in vivo andin vitro. It has also been shown that a decrease in the level of IGF-1Rbelow wild-type levels causes apoptosis of tumor cells in vivo. Theability of IGF-1R disruption to cause apoptosis appears to be diminishedin normal, non-tumorigenic cells.

Inappropriately high protein kinase activity has been implicated in manydiseases resulting from abnormal cellular function. This might ariseeither directly or indirectly by a failure of the proper controlmechanisms for the kinase, related to mutation, over-expression orinappropriate activation of the enzyme; or by an over- orunderproduction of cytokines or growth factors participating in thetransduction of signals upstream or downstream of the kinase. In all ofthese instances, selective inhibition of the action of the kinase mightbe expected to have a beneficial effect.

IGF-1R is a transmembrane RTK that binds primarily to IGF-1 but also toIGF-II and insulin with lower affinity. Binding of IGF-1 to its receptorresults in receptor oligomerization, activation of tyrosine kinase,intermolecular receptor autophosphorylation and phosphorylation ofcellular substrates (major substrates are IRS1 and Shc). Theligand-activated IGF-1R induces mitogenic activity in normal cells andplays an important role in abnormal growth.

The IGF-1 pathway in human tumor development has an important role: 1)IGF-1R overexpression is frequently found in various tumors (breast,colon, lung, sarcoma) and is often associated with an aggressivephenotype. 2) High circulating IGF1 concentrations are stronglycorrelated with prostate, lung and breast cancer risk. Furthermore,IGF-1R is required for establishment and maintenance of the transformedphenotype in vitro and in vivo (Baserga R. Exp. Cell. Res., 1999, 253,1-6). The kinase activity of IGF-1R is essential for the transformingactivity of several oncogenes: EGFR, PDGFR, SV40 T antigen, activatedRas, Raf, and v-Src. The expression of IGF-1R in normal fibroblastsinduces neoplastic phenotypes, which can then form tumors in vivo.IGF-1R expression plays an important role in anchorage-independentgrowth. IGF-1R has also been shown to protect cells from chemotherapy-,radiation-, and cytokine-induced apoptosis. Conversely, inhibition ofendogenous IGF-1R by dominant negative IGF-1R, triple helix formation orantisense expression vector has been shown to repress transformingactivity in vitro and tumor growth in animal models.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysinvolved in numerous disorders, including cancer, psoriasis, fibrosis,atherosclerosis, restenosis, auto-immune disease, allergy, asthma,transplantation rejection, inflammation, thrombosis, nervous systemdiseases, and other hyperproliferative disorders or hyper-immuneresponses. It is desirable to provide novel inhibitors of kinasesinvolved in mediating or maintaining disease states to treat suchdiseases.

The identification of effective small compounds that specificallyinhibit signal transduction and cellular proliferation, by modulatingthe activity of receptor and non-receptor tyrosine and serine/threoninekinases, to regulate and modulate abnormal or inappropriate cellproliferation, differentiation, or metabolism is therefore desirable. Inparticular, the identification of methods and compounds thatspecifically inhibit the function of a tyrosine kinase essential forangiogenic processes or for the formation of vascular hyperpermeabilityleading to edema, ascites, effusions, exudates, macromolecularextravasation, matrix deposition, and their associated disorders wouldbe beneficial.

It has been recognized that inhibitors of protein-tyrosine kinases areuseful as selective inhibitors of the growth of mammalian cancer cells.For example, Gleevec™ (also known as imatinib mesylate, or STI571), a2-phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinaseactivity of the BCR-ABL fusion gene product, was recently approved bythe U.S. Food and Drug Administration for the treatment of CML. Thiscompound, in addition to inhibiting BCR-ABL kinase, also inhibits KITkinase and PDGF receptor kinase, although it is not effective againstall mutant isoforms of KIT kinase. In recent clinical studies on the useof Gleevec™ to treat patients with GIST, a disease in which KIT kinaseis involved in transformation of the cells, many of the patients showedmarked clinical improvement. Other kinase inhibitors show even greaterselectively. For example, the 4-anilinoquinazoline compound Tarceva™inhibits only EGF receptor kinase with high potency, although it caninhibit the signal transduction of other receptor kinases, probablybecause such receptors heterodimerize with the EGF receptor.

In view of the importance of PTKs to the control, regulation, andmodulation of cell proliferation and the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify small molecule tyrosine kinase inhibitors. Bis-,mono-cyclic, bicyclic or heterocyclic aryl compounds (InternationalPatent Publication No. WO 92/20642) and vinylene-azaindole derivatives(International Patent Publication No. WO 94/14808) have been describedgenerally as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No.5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No.5,302,606), certain quinazoline derivatives (EP Application No. 0566266A1; Expert Opin. Ther. Pat. (1998), 8(4): 475-478), selenoindoles andselenides (International Patent Publication No. WO 94/03427), tricyclicpolyhydroxylic compounds (International Patent Publication No. WO92/21660) and benzylphosphonic acid compounds (International PatentPublication No. WO 91/15495) have been described as compounds for use astyrosine kinase inhibitors for use in the treatment of cancer.Anilinocinnolines (PCT WO97/34876) and quinazoline derivative compounds(International Patent Publication No. WO 97/22596; International PatentPublication No. WO97/42187) have been described as inhibitors ofangiogenesis and vascular permeability. Bis(indolylmaleimide) compoundshave been described as inhibiting particular PKC serine/threonine kinaseisoforms whose signal transducing function is associated with alteredvascular permeability in VEGF-related diseases (International PatentPublication Nos. WO 97/40830 and WO 97/40831).

International Patent Publication Nos. WO 03/018021 and WO 03/018022describe pyrimidines for treating IGF-1R related disorders,International Patent Publication Nos. WO 02/102804 and WO 02/102805describe cyclolignans and cyclolignans as IGF-1R inhibitors,International Patent Publication No. WO 02/092599 describespyrrolopyrimidines for the treatment of a disease which responds to aninhibition of the IGF-1R tyrosine kinase, International PatentPublication No. WO 01/72751 describes pyrrolopyrimidines as tyrosinekinase inhibitors. International Patent Publication No. WO 00/71129describes pyrrolotriazine inhibitors of kinases. International PatentPublication No. WO 97/28161 describes pyrrolo[2,3-d]pyrimidines andtheir use as tyrosine kinase inhibitors.

Parrizas, et al. describes tyrphostins with in vitro and in vivo IGF-1Rinhibitory activity (Endocrinology, 138:1427-1433 (1997)), andInternational Patent Publication No. WO 00/35455 describesheteroaryl-aryl ureas as IGF-1R inhibitors. International PatentPublication No. WO 03/048133 describes pyrimidine derivatives asmodulators of IGF-1R. International Patent Publication No. WO 03/024967describes chemical compounds with inhibitory effects towards kinaseproteins. International Patent Publication No. WO 03/068265 describesmethods and compositions for treating hyperproliferative conditions.International Patent Publication No. WO 00/17203 describespyrrolopyrimidines as protein kinase inhibitors. Japanese PatentPublication No. JP 07/133,280 describes a cephem compound, itsproduction and antimicrobial composition. A. Albert et al., Journal ofthe Chemical Society, 11: 1540-1547 (1970) describes pteridine studiesand pteridines unsubstituted in the 4-position, a synthesis frompyrazines via 3-4-dhydropteridines. A. Albert et al., Chem. Biol.Pteridines Proc. Int. Symp., 4th, 4: 1-5 (1969) describes a synthesis ofpteridines (unsubstituted in the 4-position) from pyrazines, via3-4-dihydropteridines.

IGF-1R performs important roles in cell division, development, andmetabolism, and in its activated state, plays a role in oncogenesis andsuppression of apoptosis. IGF-1R is known to be overexpressed in anumber of cancer cell lines (IGF-1R overexpression is linked toacromegaly and to cancer of the prostate). By contrast, down-regulationof IGF-1R expression has been shown to result in the inhibition oftumorigenesis and an increased apoptosis of tumor cells.

Although the anticancer compounds described above have made asignificant contribution to the art, there is a continuing need in thisfield of art to improve anticancer pharmaceuticals with betterselectivity or potency, reduced toxicity, or fewer side effects.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt thereof. The compounds of FormulaI inhibit the IGF-1R enzyme and are useful for the treatment and/orprevention of hyperproliferative diseases such as cancer, inflammation,psoriasis, allergy/asthma, disease and conditions of the immune system,disease and conditions of the central nervous system.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X₁, and X₂ are each independently N or C-(E¹)_(aa);

X₅ is N, C-(E¹)_(aa), or N-(E¹)_(aa);

X₃, X₄, X₆, and X₇ are each independently N or C;

-   -   wherein at least one of X₃, X₄, X₅, X₆, and X₇ is independently        N or N-(E¹)_(aa);

Q¹ is

X₁₁, X₁₂, X₁₃, X₁₄, X₁₅, and X₁₆ are each independently N, C-(E¹¹)_(bb),or N⁺—O⁻;

wherein at least one of X₁₁, X₁₂, X₁₃, X₁₄, X₁₅, and X₁₆ is N or N⁺—O⁻;

R¹ is absent, C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocyclyl,heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl, any of whichis optionally substituted by one or more independent G¹¹ substituents;

E¹, E¹¹, G¹, and G⁴¹ are each independently halo, —CF₃, —OCF₃, —OR²,—NR²R³(R^(2a))_(j1), —C(═O)R², —CO₂R², —CONR²R³, —NO₂, —CN,—S(O)_(j1)R², —SO₂NR²R³, —NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a),—NR²S(O)_(j1)R³, —C(═S)OR², —C(═O)SR², —NR²C(═NR³)NR^(2a)R^(3a),—NR²C(═NR³)OR^(2a), —NR²C(═³)SR^(2a), —OC(═O)OR², —OC(═O)NR²R³,—OC(═O)SR², —SC(═O)OR², —SC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenyl₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents;

or E¹, E¹¹, or G¹ optionally is —(W¹)_(n)—(Y¹)_(m)—R⁴;

or E¹, E¹¹, G¹, or G⁴¹ optionally independently is aryl-C₀₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—C(═O)NR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents;

G¹¹ is halo, oxo, —CF₃, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —NO₂, —CN, —S(O)_(j4)R²¹, —SO₂NR²¹R³¹,NR²¹(C═O)R³¹, NR²¹C(═O)OR³¹, NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹,—C(═S)OR²¹, —C(═O)SR²¹, —NR²¹C(═NR³¹)NR^(2a1)R^(3a1),—NR²¹C(═NR³¹OR^(2a1), —NR²¹C(═NR³¹)SR^(2a1), —OC(═O)OR²¹,—C(═O)NR²¹NR³¹. —OC(═O)SR²¹, —SC(═O)OR²¹, —SC(═O)NR²¹R³¹, —P(O)OR²¹OR³¹,C₁₋₁₀alkylidene, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈ alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenyl C₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, or hetaryl-C₂₋₁₀alkynyl, or hetaryl-C₂₋₁₀alkynyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a),—C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents;

or G¹¹ is C, taken together with the carbon to which it is attachedforms a C═C double bond which is substituted with R⁵ and G¹¹¹;

R², R^(2a), R³, R^(3a), R²²², R^(222a), R³³³, R^(333a), R²¹, R^(2a1),R³¹, R^(3a1), R²²²¹, R^(222a1), R³³³¹, and R^(333a1) are eachindependently C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted by one ormore independent G¹¹¹ substituents;

or in the case of —NR²R³(R^(2a))_(j1) or —NR²²²R³³³(R^(222a))_(j1a) or—NR²²²R³³³(R^(222a))_(j2a) or —NR²¹R³¹(R^(2a1))_(j4) or—NR²²²¹R³³³¹(R^(222a1))_(j4a) or —NR²²²¹R³³³¹(R^(222a1))_(j5a), then R²and R³, or R²²² and R³³³, or R²²²¹ and R³³³¹, respectfully, areoptionally taken together with the nitrogen atom to which they areattached to form a 3-10 membered saturated or unsaturated ring, whereinsaid ring is optionally substituted by one or more independent G¹¹¹¹substituents and wherein said ring optionally includes one or moreheteroatoms other than the nitrogen to which R² and R³, or R²²² andR³³³, or R²²²¹ and R³³³¹ are attached;

W¹ and Y¹ are each independently —O—, —NR⁷—, —S(O)_(j7)—, —CR⁵R⁶—,—N(C(O)OR⁷)—, —N(C(O)R⁷)—, —N(SO₂R⁷)—, —CH₂O—, —CH₂S—, —CH₂N(R⁷)—,—CH(NR⁷)—, —CH₂N(C(O)R⁷)—, —CH₂N(C(O)OR⁷)—, —CH₂N(SO₂R⁷)—, —CH(NHR⁷)—,—CH(NHC(O)R⁷)—, —CH(NHSO₂R⁷)—, —CH(NHC(O)OR⁷)—, —CH(OC(O)R⁷)—,—CH(OC(O)NHR⁷)—, —CH═CH—, —C≡C—, —C(═NOR⁷)—, —C(O)—, —CH(OR⁷)—,—C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂— —OC(O)N(R⁷)—,—N(R⁷)C(O)N(R⁸)—, —NR⁷C(O)O—, —S(O)N(R⁷)—, —S(O)₂N(R⁷)—,—N(C(O)R⁷)S(O)—, —N(C(O)R⁷)S(O)₂—, —N(R⁷)S(O)N(R⁸)—, —N(R⁷)S(O)₂N(R⁸)—,—C(O)N(R⁷)C(O)—, —S(O)N(R⁷)C(O)—, —S(O)₂N(R⁷)C(O)—, —OS(O)N(R⁷)—,—OS(O)₂N(R⁷)—, —N(R⁷)S(O)O—, —N(R⁷)S(O)₂O—, —N(R⁷)S(O)C(O)—,—N(R⁷)S(O)₂C(O)—, —SON(C(O)R⁷)—, —SO₂N(C(O)R⁷)—, —N(R⁷)SON(R⁸)—,—N(R⁷)SO₂N(R⁸)—, —C(O)O—, —N(R⁷)P(OR⁸)O—, —N(R⁷)P(OR⁸)—,—N(R⁷)P(O)(OR⁸)O—, —N(R⁷)P(O)(OR⁸)—, —N(C(O)R⁷)P(OR⁸)O—,—N(C(O)R⁷)P(OR⁸)—, —N(C(O)R⁷)P(O)(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—,—CH(R⁷)S(O)—, —CH(R⁷)S(O)₂—, —CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—,—CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)O—, —CH(R⁷)S—, —CH(R⁷)N(R⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(SO₂R⁸)—,—CH(R⁷)C(═NOR⁸)—, —CH(R⁷)C(O)—, —CH(R⁷)CH(OR⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, —CH(R⁷)N(R⁸)S(O)₂—,—CH(R⁷)OC(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)N(R^(7a))—, —CH(R⁷)NR⁸C(O)O—,—CH(R⁷)S(O)N(R⁸)—, —CH(R⁷)S(O)₂N(R⁸)—, —CH(R⁷)N(C(O)R⁸)S(O)—,—CH(R⁷)N(C(O)R⁸)S(O)—, —CH(R⁷)N(R⁸)S(O)N(R^(7a))—,—CH(R⁷)N(R⁸)S(O)₂N(R^(7a))—, —CH(R⁷)C(O)N(R⁸)C(O)—,—CH(R⁷)S(O)N(R⁸)C(O)—, —CH(R⁷)S(O)₂N(R⁸)C(O)—, —CH(R⁷)OS(O)N(R⁸)—,—CH(R⁷)OS(O)₂N(R⁸)—, —CH(R⁷)N(R⁸)S(O)O—, —CH(R⁷)N(R⁸)S(O)₂O—,—CH(R⁷)N(R⁸)S(O)C(O)—, —CH(R⁷)N(R⁸)S(O)₂C(O)—, —CH(R⁷)SON(C(O)R⁸)—,—CH(R⁷)SO₂N(C(O)R⁸)—, —CH(R⁷)N(R⁸)SON(R^(7a))—,—CH(R⁷)N(R⁸)SO₂N(R^(7a))—, —CH(R⁷)C(O)O—, —CH(R⁷)N(R⁸)P(OR^(7a))O—,—CH(R⁷)N(R⁸)P(OR^(7a))—, —CH(R⁷)N(R⁸)P(O)(OR^(7a))O—,—CH(R⁷)N(R⁸)P(O)(OR^(7a))—, —CH(R⁷)N(C(O)R⁸)P(OR^(7a))O—,—CH(R⁷)N(C(O)R⁸)P(OR^(7a))—, —CH(R⁷)N(C(O)R⁸)P(O)(OR^(7a))O—, or—CH(R⁷)N(C(O)R⁸)P(OR^(7a))—;

R⁵, R⁶, G¹¹¹, and G¹¹¹¹ are each independently C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷,—CONR⁷⁷R⁸⁷, —NO₂, —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, —NR⁷⁷C(═O)R⁸⁷,—NR⁷⁷C(═O)OR⁸⁷, —NR⁷⁷C(═O)NR⁷⁸R⁸⁷, —NR⁷⁷S(O)_(j5a)R⁸⁷, —C(═S)OR⁷⁷,—C(═O)SR⁷⁷, —NR⁷⁷C(═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷C(═NR⁸⁷)OR⁷⁸, —NR⁷⁷C(═NR⁸⁷)SR⁷⁸,—OC(═O)OR⁷⁷, —OC(═O)NR⁷⁷R⁸⁷, —OC(═O)SR⁷⁷, —SC(═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or—SC(═O)NR⁷⁷R⁸⁷ substituents;

or R⁵ with R⁶ are optionally taken together with the carbon atom towhich they are attached to form a 3-10 membered saturated or unsaturatedring, wherein said ring is optionally substituted with one or moreindependent R⁶⁹ substituents and wherein said ring optionally includesone or more heteroatoms;

R⁷, R^(7a), and R⁸ are each independently acyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or cycloC₃₋₁₀alkyl, any ofwhich is optionally substituted by one or more independent G¹¹¹substituents;

R⁴ is C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₈alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents;

R⁶⁹ is halo, —OR⁷⁸, —SH, —NR⁷⁸R⁸⁸, —CO₂R⁷⁸, —C(═O)NR⁷⁸R⁸⁸, —NO₂, —CN,—S(O)_(j8)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or—NR⁷⁷⁸R⁸⁸⁸ substituents;

or R⁶⁹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl,mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₁₀alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or—N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —C(═O)NR⁷⁷⁸R⁸⁸⁸,—SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents;

or in the case of —NR⁷⁸R⁸⁸, R⁷⁸ and R⁸⁸ are optionally taken togetherwith the nitrogen atom to which they are attached to form a 3-10membered saturated or unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents, and wherein saidring optionally includes one or more heteroatoms other than the nitrogento which R⁷⁸ and R⁸⁸ are attached;

R⁷⁷, R⁷⁸, R⁸⁷, R⁸⁸, R⁷⁷⁸, and R⁸⁸⁸ are each independently C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which isoptionally substituted with one or more independent halo, cyano,hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents;

or R⁷⁷, R⁷⁸, R⁸⁷, R⁸⁸, R⁷⁷⁸, and R⁸⁸⁸ are each independentlyaryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl,mono(C₁₋₆ alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆ alkyl, di(aryl)aminoC₁₋₆ alkyl, or—N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, halo C₂₋₁₀alkynyl, —CO OH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents;

n, m, j1, j1a, j2a, j4, j4a, j5a, j7, and j8 are each independently 0,1, or 2; and

aa and bb are each independently 0 or 1.

In an aspect of the present invention, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein X₃ isN; X₁, X₂, and X₅ are C-(E¹)_(aa); X₄, X₆, and X₇ are C; and the othervariables are described as above for Formula I.

In a second aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein X₄is N; X₁, X₂, and X₅ are C-(E¹)_(aa); and X₃, X₆, and X₇ are C; and theother variables are described as above for Formula I.

In a third aspect of the present invention, a compound is represented byFormula I, or a salt thereof, wherein X₅ is N-(E¹)_(aa); X₁ and X₂ areC-(E¹)_(aa); X₃, X₄, X₆, and X₇ are C; and the other variables aredescribed as above for Formula I.

In a fourth aspect of the present invention, a compound is representedby Formula I, or a salt thereof, wherein X₆ is N; X₁, X₂, and X₅ areC-(E¹)_(aa); X₃, X₄, and X₇ are C; and the other variables are describedas above for Formula I.

In a fifth aspect of the present invention, a compound is represented byFormula I, or a salt thereof, wherein X₇ is N; X₁, X₂, and X₅ areC-(E¹)_(aa); X₃, X₄, and X₆ are C; and the other variables are describedas above for Formula I.

In a sixth aspect of the present invention, a compound is represented byFormula I, or a salt thereof, wherein X₁ and X₃ are N; X₂ and X₅ areC-(E¹)_(aa); X₄, X₆, and X₇ are C; and the other variables are describedas above for Formula I.

In a seventh aspect of the present invention, a compound is representedby Formula I, or a salt thereof, wherein X₁ and X₄ are N; X₂ and X₅ areC-(E¹)_(aa); X₃, X₆, and X₇ are C; and the other variables are describedas above for Formula I.

In an eighth aspect of the present invention, a compound is representedby Formula I, or a salt thereof, wherein X₁ is N; X₅ is N-(E¹)_(aa); X₂is C-(E¹)_(aa); X₃, X₄, X₆, and X₇ are C; and the other variables aredescribed as above for Formula I.

In a ninth aspect of the present invention, a compound is represented byFormula I, or a salt thereof, wherein X₁ and X₆ are N; X₂ and X₅ areC-(E¹)_(aa); X₃, X₄, and X₇ are C; and the other variables are describedas above for Formula I.

In a tenth aspect of the present invention, a compound is represented byFormula I, or a salt thereof, wherein X₁ and X₇ are N; X₂ and X₅ areC-(E¹)_(aa); X₃, X₄, and X₆ are C; and the other variables are describedas above for Formula I.

In a eleventh aspect of the present invention, a compound is representedby Formula I, or a salt thereof, wherein X₂ and X₃ are N; X₁ and X₅ areC-(E¹)_(aa); X₄, X₆, and X₇ are C; and the other variables are describedas above for Formula I.

In a twelfth aspect of the present invention, a compound is representedby Formula I, or a salt thereof, wherein X₂ and X₄ are N; X₁ and X₅ areC-(E¹)_(aa); X₃, X₆, and X₇ are C; and the other variables are describedas above for Formula I.

In a thirteenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂ is N; X₅ isN-(E¹)_(aa), X₁ is C-(E¹)_(aa); X₃, X₄, X₆, and X₇ are C; and the othervariables are described as above for Formula I.

In a fourteenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂ and X₆ are N; X₁and X₅ are C-(E¹)_(aa); X₃, X₄, and X₇ are C; and the other variablesare described as above for Formula I.

In a fifteenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂ and X₇ are N; X₁and X₅ are C-(E¹)_(aa); X₃, X₄, and X₆ are C; and the other variablesare described as above for Formula I.

In a sixteenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₃ and X₄ are N;X₁, X₂, and X₅ are C-(E¹)_(aa); X₆ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a seventeenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₃ and X₅ are N; X₁and X₂ are C-(E¹)_(aa); X₄, X₆, and X₇ are C; and the other variablesare described as above for Formula I.

In an eighteenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₄ and X₅ are N; X₁and X₂ are C-(E¹)_(aa); X₃, X₆, and X₇ are C; and the other variablesare described as above for Formula I.

In a nineteenth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₄ and X₆ are N;X₁, X₂, and X₅ are C-(E¹)_(aa); X₃ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a twentieth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₄ and X₇ are N;X₁, X₂, and X₅ are C-(E¹)_(aa); X₃ and X₆ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a twenty-first aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₅ and X₆ are N; X₁and X₂ are C-(E¹)_(aa), X₃, X₄, and X₇ are C; and the other variablesare described as above for Formula I.

In a twenty-second aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₅ and X₇ are N; X₁and X₂ are C-(E¹)_(aa); X₃, X₄, and X₆ are C; and the other variablesare described as above for Formula I.

In a twenty-third aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₃, and X₄ areN; X₁ and X₅ are C-(E¹)_(aa); X₆ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a twenty-fourth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₃, and X₅ areN; X₁ is C-(E¹)_(aa); X₄, X₆ and X₇ are C; and the other variables aredescribed as above for Formula I.

In a twenty-fifth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₃, X₄, and X₅ areN; X₁ and X₂ are C-(E¹)_(aa); X₆ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a twenty-sixth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₃, and X₄ areN; X₂ and X₅ are C-(E¹)_(aa); X₆ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a twenty-seventh aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₄, and X₅ areN; X₂ is C-(E¹)_(aa); X₃, X₆ and X₇ are C; and the other variables aredescribed as above for Formula I.

In a twenty-eighth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₄, and X₅ areN; X₁ is C-(E¹)_(aa); X₃, X₆ and X₇ are C; and the other variables aredescribed as above for Formula I.

In a twenty-ninth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₅, and X₆ areN; X₂ is C-(E¹)_(aa); X₃, X₄, and X₇ are C; and the other variables aredescribed as above for Formula I.

In a thirtieth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₅, and X₆ areN; X₁ is C-(E¹)_(aa); X₃, X₄, and X₇ are C; and the other variables aredescribed as above for Formula I.

In a thirty-first aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₄, X₅, and X₆ areN; X₁ and X₂ are C-(E¹)_(aa); X₃ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a thirty-second aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₃, and X₅ areN; X₂ is C-(E¹)_(aa); X₄, X₆ and X₇ are C; and the other variables aredescribed as above for Formula I.

In a thirty-third aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₄, and X₆ areN; X₂ and X₅ are C-(E¹)_(aa); X₃ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a thirty-fourth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₅, and X₇ areN; X₂ is C-(E¹)_(aa); X₃, X₄, and X₆ are C; and the other variables aredescribed as above for Formula I.

In a thirty-fifth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₄, and X₇ areN; X₂ and X₅ are C-(E¹)_(aa); X₃ and X₆ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a thirty-sixth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₄, and X₆ areN; X₁ and X₅ are C-(E¹)_(aa); X₃ and X₇ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a thirty-seventh aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₄, and X₇ areN; X₁ and X₅ are C-(E¹)_(aa); X₃ and X₆ are C; R¹ is absent; and theother variables are described as above for Formula I.

In a thirty-eighth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₅, and X₇ areN; X₁ is C-(E¹)_(aa); X₃, X₄, and X₆ are C; and the other variables aredescribed as above for Formula I.

In a thirty-ninth aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₄, X₅, and X₆are N; X₂ is C-(E¹)_(aa); X₃ and X₇ are C; R¹ is absent; and the othervariables are described as above for Formula I.

In a fortieth aspect of the present invention, a compound is representedby Formula I, or a salt thereof, wherein X₂, X₄, X₅, and X₆ are N; X₁ isC-(E¹)_(aa); X₃ and X₇ are C; R¹ is absent; and the other variables aredescribed as above for Formula I.

In a forty-first aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₁, X₃, X₄, and X₅are N; X₂ is C-(E¹)_(aa); X₆ and X₇ are C; R¹ is absent; and the othervariables are described as above for Formula I.

In a forty-second aspect of the present invention, a compound isrepresented by Formula I, or a salt thereof, wherein X₂, X₃, X₄, and X₅are N; X₁ is C-(E¹)_(aa); X₆ and X₇ are C; R¹ is absent; and the othervariables are described as above for Formula I.

The following embodiments refer to all of the forty-two aspects above:

In an embodiment of each of the above aspects, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, whereinX₁₁, X₁₂, and X₁₃ are N; X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₂, and X₁₄ are N; X₁₃, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₂, and X₁₅ are N; X₁₃, X₁₄, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₂, and X₁₆ are N; X₁₃, X₁₄, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₃, and X₁₄ are N; X₁₂, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet still another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₁, X₁₃, and X₁₅ are N; X₁₂, X₁₄, and X₁₆ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₃, and X₁₆ are N; X₁₂, X₁₄, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₄, and X₁₅ are N; X₁₂, X₁₃, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₄, and X₁₆ are N; X₁₂, X₁₃, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁, X₁₅, and X₁₆ are N; X₁₂, X₁₃, and X₁₄ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet still another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₂, X₁₃, and X₁₄ are N; X₁₁, X₁₅, and X₁₆ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In still yet another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₂, X₁₃, and X₁₅ are N; X₁₁, X₁₄, and X₁₆ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂, X₁₃, and X₁₆ are N; X₁₁, X₁₄, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂, X₁₄, and X₁₅ are N; X₁₁, X₁₃, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂, X₁₄, and X₁₆ are N; X₁₁, X₁₃, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet still another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₂, X₁₅, and X₁₆ are N; X₁₁, X₁₃, and X₁₄ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₃, X₁₄, and X₁₅ are N; X₁₁, X₁₂, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₃, X₁₄, and X₁₆ are N; X₁₁, X₁₂, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₄, X₁₅, and X₁₆ are N; X₁₁, X₁₂, and X₁₃ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₃, X₁₅, and X₁₆ are N; X₁₁, X₁₂, and X₁₄ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet still another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₁ and X₁₂ are N; X₁₃, X₁₄, X₁₅, and X₁₆ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁ and X₁₃ are N; X₁₂, X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁ and X₁₄ are N; X₁₂, X₁₃, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still yet another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₁ and X₁₅ are N; X₁₂, X₁₃, X₁₄, and X₁₆ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In yet another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁ and X₁₆ are N; X₁₂, X₁₃, X₁₄, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂ and X₁₃ are N; X₁₁, X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂ and X₁₄ are N; X₁₁, X₁₃, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂ and X₁₅ are N; X₁₁, X₁₃, X₁₄, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still yet another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₂ and X₁₆ are N; X₁₁, X₁₃, X₁₄, and X₁₅ areC-(E¹¹)_(bb); and the other variables are as described in each of theabove aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₃ and X₁₄ are N; X₁₁, X₁₂, X₁₅, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In yet still another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₃ and X₁₅ are N; X₁₁, X₁₂, X₁₄, and X₁₆ areC-(E¹¹)^(bb); and the other variables are as described in each of theabove aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₃ and X₁₆ are N; X₁₁, X₁₂, X₁₄, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₄ and X₁₅ are N; X₁₁, X₁₂, X₁₃, and X₁₆ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₄ and X₁₆ are N; X₁₁, X₁₂, X₁₃, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₅ and X₁₆ are N; X₁₁, X₁₂, X₁₃, and X₁₄ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

In another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁ is N; X₁₂, X₁₃, X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

In yet another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₂ is N; X₁₁, X₁₃, X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₃ is N; X₁₁, X₁₂, X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

In yet still another embodiment of each of the above aspects, a compoundis represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁₄ is N; X₁₁, X₁₂, X₁₃, X₁₅, and X₁₆ are C-(E¹¹)_(bb);and the other variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₅ is N; X₁₁, X₁₂, X₁₃, X₁₄, and X₁₆ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

In still another embodiment of each of the above aspects, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₆ is N; X₁₁, X₁₂, X₁₃, X₁₄, and X₁₅ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

Advantageous embodiments of the above aspects include:

An embodiment of each of the above aspects, wherein a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁ and X₁₆ are N; X₁₂, X₁₃, X₁₄, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

An embodiment of each of the above aspects, wherein a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₄ and X₁₆ are N; X₁₁, X₁₂, X₁₃, and X₁₅ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

An embodiment of each of the above aspects, wherein a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₅ and X₁₆ are N; X₁₁, X₁₂, X₁₃, and X₁₄ are C-(E¹¹)_(bb); andthe other variables are as described in each of the above aspects.

An embodiment of each of the above aspects, wherein a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₁ is N; X₁₂, X₁₃, X₁₄, X₁₅, and X₁₆ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

An embodiment of each of the above aspects, wherein a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁₆ is N; X₁₁, X₁₂, X₁₃, X₁₄, and X₁₅ are C-(E¹¹)_(bb); and theother variables are as described in each of the above aspects.

The compounds of the present invention include compounds represented byFormula I above, or a pharmaceutically acceptable salt thereof, and

wherein X₃ is N; X₁, X₂, and X₅ are C-(E¹)_(aa); and X₄, X₆, and X₇ areC; or

wherein X₄ is N; X₁, X₂, and X₅ are C-(E¹)_(aa); and X₃, X₆, and X₇ areC; or

wherein X₅ is N-(E¹)_(aa); X₁ and X₂ are C-(E¹)_(aa); and X₃, X₄, X₆,and X₇ are C; or

wherein X₆ is N; X₁, X₂, and X₅ are C-(E¹)_(aa); and X₃, X₄, and X₇ areC; or

wherein X₇ is N; X₁, X₂, and X₅ are C-(E¹)_(aa); and X₃, X₄, and X₆ areC; or

wherein X₁ and X₃ are N; X₂ and X₅ are C-(E¹)_(aa); and X₄, X₆, and X₇are C; or

wherein X₁ and X₄ are N; X₂ and X₅ are C-(E¹)_(aa); and X₃, X₆, and X₇are C; or

wherein X₁ is N; X₅ is N-(E¹)_(aa); X₂ is C-(E¹)_(aa); and X₃, X₄, X₆,and X₇ are C; or

wherein X₁ and X₆ are N; X₂ and X₅ are C-(E¹)_(aa); and X₃, X₄, and X₇are C; or

wherein X₁ and X₇ are N; X₂ and X₅ are C-(E¹)_(aa); and X₃, X₄, and X₆are C; or

wherein X₂ and X₃ are N; X₁ and X₅ are C-(E¹)_(aa); and X₄, X₆, and X₇are C; or

wherein X₂ and X₄ are N; X₁ and X₅ are C-(E¹)_(aa); and X₃, X₆, and X₇are C; or

wherein X₂ is N; X₅ is N-(E¹)_(aa), X₁ is C-(E¹)_(aa); and X₃, X₄, X₆,and X₇ are C; or

wherein X₂ and X₆ are N; X₁ and X₅ are C-(E¹)_(aa); and X₃, X₄, and X₇are C; or

wherein X₂ and X₇ are N; X₁ and X₅ are C-(E¹)_(aa); and X₃, X₄, and X₆are C; or

wherein X₃ and X₄ are N; X₁, X₂, and X₅ are C-(E¹)_(aa); X₆ and X₇ areC; and R¹ is absent; or

wherein X₃ and X₅ are N; X₁ and X₂ are C-(E¹)_(aa); and X₄, X₆, and X₇are C; or

wherein X₄ and X₅ are N; X₁ and X₂ are C-(E¹)_(aa); and X₃, X₆, and X₇are C; or

wherein X₄ and X₆ are N; X₁, X₂, and X₅ are C-(E¹)_(aa); X₃ and X₇ areC; and R¹ is absent; or

wherein X₄ and X₇ are N; X₁, X₂, and X₅ are C-(E¹)_(aa); X₃ and X₆ areC; and R¹ is absent; or

wherein X₅ and X₆ are N; X₁ and X₂ are C-(E¹)_(aa); and X₃, X₄, and X₇are C; or

wherein X₅ and X₇ are N; X₁ and X₂ are C-(E¹)_(aa); and X₃, X₄, and X₆are C; or

wherein X₂, X₃, and X₄ are N; X₁ and X₅ are C-(E¹)_(aa); X₆ and X₇ areC; and R¹ is absent; or

wherein X₂, X₃, and X₅ are N; X₁ is C-(E¹)_(aa); and X₄, X₆ and X₇ areC; or

wherein X₃, X₄, and X₅ are N; X₁ and X₂ are C-(E¹)_(aa); X₆ and X₇ areC; and R¹ is absent; or

wherein X₁, X₃, and X₄ are N; X₂ and X₅ are C-(E¹)_(aa); X₆ and X₇ areC; and R¹ is absent; or

wherein X₁, X₄, and X₅ are N; X₂ is C-(E¹)_(aa); and X₃, X₆, and X₇ areC; or

wherein X₂, X₄, and X₅ are N; X₁ is C-(E¹)_(aa); and X₃, X₆, and X₇ areC; or

wherein X₁, X₅, and X₆ are N; X₂ is C-(E¹)_(aa); and X₃, X₄, and X₇ areC; or

wherein X₂, X₅, and X₆ are N; X₁ is C-(E¹)_(aa); and X₃, X₄, and X₇ areC; or

wherein X₄, X₅, and X₆ are N; X₁ and X₂ are C-(E¹)_(aa); X₃ and X₇ areC; and

R¹ is absent; or

wherein X₁, X₃, and X₅ are N; X₂ is C-(E¹)_(aa), and X₄, X₆, and X₇ areC; or

wherein X₁, X₄, and X₆ are N; X₂ and X₅ are C-(E¹)_(aa); X₃ and X₇ areC; and R¹ is absent; or

wherein X₁, X₅, and X₇ are N; X₂ is C-(E¹)_(aa); and X₃, X₄, and X₆ areC; or

wherein X₁, X₄, and X₇ are N; X₂ and X₅ are C-(E¹)_(aa); X₃ and X₆ areC; and R¹ is absent; or

wherein X₂, X₄, and X₆ are N; X₁ and X₅ are C-(E¹)_(aa); X₃ and X₇ areC; and R¹ is absent; or

wherein X₂, X₄, and X₇ are N; X₁ and X₅ are C-(E¹)_(aa); X₃ and X₆ areC; and R¹ is absent; or

wherein X₂, X₅, and X₇ are N; X₁ is C-(E¹)_(aa); and X₃, X₄, and X₆ areC; or

wherein X₁, X₄, X₅, and X₆ are N; X₂ is C-(E¹)_(aa); X₃ and X₇ are C;and R¹ is absent; or

wherein X₂, X₄, X₅, and X₆ are N; X₁ is C-(E¹)_(aa); X₃ and X₇ are C;and R¹ is absent; or

wherein X₁, X₃, X₄, and X₅ are N; X₂ is C-(E¹)_(aa); X₆ and X₇ are C;and R¹ is absent; or

wherein X₂, X₃, X₄, and X₅ are N; X₁ is C-(E¹)_(aa); X₆ and X₇ are C;and R¹ is absent; or

wherein any one of X₁₁₋₁₆ is N; or

wherein any two of X₁₁₋₁₆ is N; or

wherein any three of X₁₁₋₁₆ is N; or

wherein any one of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₄, X₁₅, or X₁₆ is N; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is C₀₋₁₀alkyl, cycloC₃₋₈alkyl, or heterocyclyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²²,—CO₂R²²², —C(═O)NR²²²R³³³, —NO₂, —CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—C(═O)NR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₆ is N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein R¹ is C₀₋₁₀alkyl, heteroaralkyl, or aralkyl, any of which isoptionally substituted by one or more independent G¹ substituents; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein R¹ is heterocyclyl or heterobicycloC₅₋₁₀alkyl, of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G¹¹ substituents; or

wherein R¹ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl cycloC₃₋₈alkylC₁₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹,—NR²¹C(═O)OR³¹—NR²¹C(═O)R³¹NR^(2a1), —NR²¹S(O)_(j4)R³¹, OC(═O)OR²¹R³¹,C₀₋₁₀alkyl, C₁₋₁₀alkoxy, C₁₋₁₀alkyl cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —OR²²²¹, —NR²²²¹R³³³¹(R^(22a1))_(j4a)substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo,—OR²²²¹,or —NR²²²¹R³³³¹(R^(222a1))_(j4a) substituents; or G¹¹ ishetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein any one of X₁₁₋₁₆ is N; or

wherein any two of X₁₁₋₁₆ is N; or

wherein any three of X₁₁₋₁₆ is N; or

wherein any one of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₄, X₁₅, or X₁₆ is N; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is C₀₋₁₀alkyl, cycloC₃₋₈alkyl, or heterocyclyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²²,—CO₂R²²², —C(═O)NR²²²R³³³, —NO₂, —CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—C(═O)NR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₆ is N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein R¹ is C₀₋₁₀alkyl, heteroaralkyl, or aralkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein R¹ is heterocyclyl or heterobicycloC₅₋₁₀alkyl, of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G¹¹ substituents; or

wherein R¹ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹, —CO₂R²¹,—C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₀₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, heterocycyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹)NR^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —OR²²²¹, or —NR²²²¹R³³³¹(R^(222a1))_(j4a)substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —OR²²²¹,or —NR²²²¹R³³³¹(R^(222a1))_(j4a) substituents; or G¹¹ ishetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹, —NO₂, —CN,—S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₀₋₁₀alkoxyC₀₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein any one of X₁₁₋₁₆ is N; or

wherein any two of X₁₁₋₁₆ is N; or

wherein any three of X₁₁₋₁₆ is N; or

wherein any one of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁), X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₄, X₁₅, or X₁₆ is N; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is C₀₋₁₀alkyl, cycloC₃₋₈alkyl, or heterocyclyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²²,—CO₂R²²², —C(═O)NR²²²R³³³, —NO₂, —CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—C(═O)NR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₆ is N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein R¹ is C₀₋₁₀alkyl, heteroaralkyl, or aralkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein R¹ is heterocyclyl or heterobicycloC₅₋₁₀alkyl, of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G¹¹ substituents; or

wherein R¹ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₁₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a)substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more one or more independent halo,oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹,—CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —OR²²²¹,or —NR²²²¹R³³³¹(R^(222a1))_(j4a) substituents, or G¹¹ ishetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein any one of X₁₁₋₁₆ is N; or

wherein any two of X₁₁₋₁₆ is N; or

wherein any three of X₁₁₋₁₆ is N; or

wherein any one of X₁₁, X₁₄, X_(is), or X₁₆ is N; or

wherein any two of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₄, X₁₅, or X₁₆ is N; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹ is —OR², —NR S(O)_(j1)R², C₁₋₁₀alkyl, cycloC₃₋₈alkyl,heterocyclyl-C₁₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is C₀₋₁₀alkyl, cycloC₃₋₈alkyl, or heterocyclyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²²,—CO₂R²²², —C(═O)NR²²²R³³³, —NO₂, —CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is aryl-C₀₋₁₀oalkyl or hetaryl-C₁₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—C(═O)NR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein X₁₆ is N; or

wherein X_(is) and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein R¹ is C₀₋₁₀alkyl, heteroaralkyl, or aralkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein R¹ is heterocyclyl or heterobicycloC₅₋₁₀alkyl, of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G¹¹ substituents; or

wherein R¹ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₀₋₁₀alkoxyC₀₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(═O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, C₀₋₁₀alkyl,C₀₋₁₀alkoxyC₀₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —OR²²²¹, or —NR²²²¹R³³³¹(R^(222a1))_(j4a)substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹R³¹,C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(═O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —OR²²²¹,or —NR²²²¹R³³³¹(R^(222a1))_(j4a) substituents; or G¹¹ is ahetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₀₋₁₀alkoxyC₀₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═O)NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein any one of X₁₁₋₁₆ is N; or

wherein any two of X₁₁₋₁₆ is N; or

wherein any three of X₁₁₋₁₆ is N; or

wherein any one of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₁, X₁₄, X₁₅, or X₁₆ is N; or

wherein any two of X₁₄, X₁₅, or X₁₆ is N; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is C₀₋₁₀alkyl, cycloC₃₋₈alkyl, or heterocyclyl-C₀₋₁₀alkyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²²,—CO₂R²²², —C(═O)NR²²²R³³³, —NO₂, —CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein G¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—C(═O)NR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²², —C(═O)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₆ is N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein R¹ is C₀₋₁₀alkyl, heteroaralkyl, or aralkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein R¹ is heterocyclyl or heterobicycloC₅₋₁₀alkyl, of which isoptionally substituted by one or more independent G¹¹ substituents; or

wherein R¹ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G¹ substituents; or

wherein R¹ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl any of which is optionally substituted by one or moreindependent G¹¹ substituents; or

wherein X₁₆ is N; or

wherein X₁₄ and X₁₆ are N; or

wherein X₁₅ and X₁₆ are N; or

wherein X₁₁ and X₁₆ are N; or

wherein X₁₁ is N; or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₀₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₁₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a)substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or

wherein G¹¹ is oxo, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —CO₂R²¹,—C(═O)NR²¹R³¹, C₀₋₁₀alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, oxo, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a) substituents; or G¹¹ ishetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j5a), —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹, —NO₂, —CN,—S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j5a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents;

wherein G¹¹ is oxo, —OCF₃, —OR²¹, —NR²¹R³¹(R^(2a1))_(j4), —C(O)R²¹,—CO₂R²¹, —C(═O)NR²¹R³¹, —CN, —SO₂NR²¹R³¹, —NR²¹(C═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(2a1), —NR²¹S(O)_(j4)R³¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,C₀₋₁₀alkoxyC₀₋₁₀alkyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,heterocyclyl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(222a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —C(═O)NR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1), —NR²²²¹S(O)_(j4a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹C(═NR³³³¹)OR^(222a1), —NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—SC(═O)NR²²²¹R³³³¹ substituents; or G¹¹ is hetaryl-C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,—C(═O)NR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(222a1),—NR²²²¹S(O)_(j5a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹C(═NR³³³¹)OR^(222a1),—NR²²²¹C(═NR³³³¹)SR^(222a1), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents; or G¹¹ is C, taken together with the carbon to which it isattached forms a C═C double bond which is substituted with R⁵ and G¹¹¹;or

wherein R¹ is cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkylany of which is optionally substituted by one or more independent G¹¹substituents; or

wherein G¹ is —OR², —NR²R³(R^(2a))_(j1), —S(O)_(j1)R², C₀₋₁₀alkyl,cycloC₃₋₈alkyl, heterocyclyl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(═O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(═O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G¹ is aryl-C₀₋₁₀alkylor hetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with oneor more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —C(═O)NR²²²R³³³, —NO₂,—CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a),—NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or

wherein, in each case, the other variables are as defined above forFormula I.

The compounds of the present invention include any one of,

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention include any one of,

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃   F; or

X Y Z CH H H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H HCF CH₃ H CF H F CF CH₃ F; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H C—CH₃ CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ HCH N H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH HH N CH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F NCF H H N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H C—CH₃ CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ HCH N H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH HH N CH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F NCF H H N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z G CH H H CH CH CH₃ H CH CH H F CH CH CH₃ F CH N H H CH N CH₃ H CHN H F CH N CH₃ F CH CF H H CH CF CH₃ H CH CF H F CH CF CH₃ F CH CH H H NCH CH₃ H N CH H F N CH CH₃ F N N H H N N CH₃ H N N H F N N CH₃ F N CF HH N CF CH₃ H N CF H F N CF CH₃ F N; or

X Y Z R CH CH₃ F CH₃ N H H CH₃ N CH₃ H CH₃ N H F CH₃ N CH₃ F CH₃ CF H HCH₃ CF CH₃ H CH₃ CF H F CH₃ CF CH₃ F CH₃ CH H H Ac CH CH₃ H Ac CH H F AcCH CH₃ F Ac N H H Ac N CH₃ H Ac N H F Ac N CH₃ F Ac CF H H Ac CF CH₃ HAc CF H F Ac CF CH₃ F Ac CH H H CO(CF₃) CH CH₃ H CO(CF₃) CH H F CO(CF₃)CH CH₃ F CO(CF₃) N H H CO(CF₃) N CH₃ H CO(CF₃) N H F CO(CF₃) N CH₃ FCO(CF₃) CF H H CO(CF₃) CF CH₃ H CO(CF₃) CF H F CO(CF₃) CF CH₃ F CO(CF₃)CH H H CO(CH₂CH₃) CH CH₃ H CO(CH₂CH₃) CH H F CO(CH₂CH₃) CH CH₃ FCO(CH₂CH₃) N H H CO(CH₂CH₃) N CH₃ H CO(CH₂CH₃) N H F CO(CH₂CH₃) N CH₃ FCO(CH₂CH₃) CF H H CO(CH₂CH₃) CF CH₃ H CO(CH₂CH₃) CF H F CO(CH₂CH₃) CFCH₃ F CO(CH₂CH₃) CH H H CO(NMe₂) CH CH₃ H CO(NMe₂) CH H F CO(NMe₂) CHCH₃ F CO(NMe₂) N H H CO(NMe₂) N CH₃ H CO(NMe₂) N H F CO(NMe₂) N CH₃ FCO(NMe₂) CF H H CO(NMe₂) CF CH₃ H CO(NMe₂) CF H F CO(NMe₂) CF CH₃ FCO(NMe₂) CH H H CO(iPr) CH CH₃ H CO(iPr) CH H F CO(iPr) CH CH₃ F CO(iPr)N H H CO(iPr) N CH₃ H CO(iPr) N H F CO(iPr) N CH₃ F CO(iPr) CF H HCO(iPr) CF CH₃ H CO(iPr) CF H F CO(iPr) CF CH₃ F CO(iPr) CH H HCO(CH₂OCH₃) CH CH₃ H CO(CH₂OCH₃) CH H F CO(CH₂OCH₃) CH CH₃ F CO(CH₂OCH₃)N H H CO(CH₂OCH₃) N CH₃ H CO(CH₂OCH₃) N H F CO(CH₂OCH₃) N CH₃ FCO(CH₂OCH₃) CF H H CO(CH₂OCH₃) CF CH₃ H CO(CH₂OCH₃) CF H F CO(CH₂OCH₃)CF CH₃ F CO(CH₂OCH₃) CH H H CO(CH₂NMe₂) CH CH₃ H CO(CH₂NMe₂) CH H FCO(CH₂NMe₂) CH CH₃ F CO(CH₂NMe₂) N H H CO(CH₂NMe₂) N CH₃ H CO(CH₂NMe₂) NH F CO(CH₂NMe₂) N CH₃ F CO(CH₂NMe₂) CF H H CO(CH₂NMe₂) CF CH₃ HCO(CH₂NMe₂) CF H F CO(CH₂NMe₂) CF CH₃ F CO(CH₂NMe₂) CH H H CO₂CH₃ CH CH₃H CO₂CH₃ CH H F CO₂CH₃ CH CH₃ F CO₂CH₃ N H H CO₂CH₃ N CH₃ H CO₂CH₃ N H FCO₂CH₃ N CH₃ F CO₂CH₃ CF H H CO₂CH₃ CF CH₃ H CO₂CH₃ CF H F CO₂CH₃ CF CH₃F CO₂CH₃ CH H H CO₂CH₂CH₃ CH CH₃ H CO₂CH₂CH₃ CH H F CO₂CH₂CH₃ CH CH₃ FCO₂CH₂CH₃ N H H CO₂CH₂CH₃ N CH₃ H CO₂CH₂CH₃ N H F CO₂CH₂CH₃ N CH₃ FCO₂CH₂CH₃ CF H H CO₂CH₂CH₃ CF CH₃ H CO₂CH₂CH₃ CF H F CO₂CH₂CH₃ CF CH₃ FCO₂CH₂CH₃ CH H H Et CH CH₃ H Et CH H F Et CH CH₃ F Et N H H Et N CH₃ HEt N H F Et N CH₃ F Et CF H H Et CF CH₃ H Et CF H F Et CF CH₃ F Et; or

X Y Z R CH CH₃ F CH₃ N H H CH₃ N CH₃ H CH₃ N H F CH₃ N CH₃ F CH₃ CF H HCH₃ CF CH₃ H CH₃ CF H F CH₃ CF CH₃ F CH₃ CH H H Ac CH CH₃ H Ac CH H F AcCH CH₃ F Ac N H H Ac N CH₃ H Ac N H F Ac N CH₃ F Ac CF H H Ac CF CH₃ HAc CF H F Ac CF CH₃ F Ac CH H H CO(CF₃) CH CH₃ H CO(CF₃) CH H F CO(CF₃)CH CH₃ F CO(CF₃) N H H CO(CF₃) N CH₃ H CO(CF₃) N H F CO(CF₃) N CH₃ FCO(CF₃) CF H H CO(CF₃) CF CH₃ H CO(CF₃) CF H F CO(CF₃) CF CH₃ F CO(CF₃)CH H H CO(CH₂CH₃) CH CH₃ H CO(CH₂CH₃) CH H F CO(CH₂CH₃) CH CH₃ FCO(CH₂CH₃) N H H CO(CH₂CH₃) N CH₃ H CO(CH₂CH₃) N H F CO(CH₂CH₃) N CH₃ FCO(CH₂CH₃) CF H H CO(CH₂CH₃) CF CH₃ H CO(CH₂CH₃) CF H F CO(CH₂CH₃) CFCH₃ F CO(CH₂CH₃) CH H H CO(NMe₂) CH CH₃ H CO(NMe₂) CH H F CO(NMe₂) CHCH₃ F CO(NMe₂) N H H CO(NMe₂) N CH₃ H CO(NMe₂) N H F CO(NMe₂) N CH₃ FCO(NMe₂) CF H H CO(NMe₂) CF CH₃ H CO(NMe₂) CF H F CO(NMe₂) CF CH₃ FCO(NMe₂) CH H H CO(iPr) CH CH₃ H CO(iPr) CH H F CO(iPr) CH CH₃ F CO(iPr)N H H CO(iPr) N CH₃ H CO(iPr) N H F CO(iPr) N CH₃ F CO(iPr) CF H HCO(iPr) CF CH₃ H CO(iPr) CF H F CO(iPr) CF CH₃ F CO(iPr) CH H HCO(CH₂OCH₃) CH CH₃ H CO(CH₂OCH₃) CH H F CO(CH₂OCH₃) CH CH₃ F CO(CH₂OCH₃)N H H CO(CH₂OCH₃) N CH₃ H CO(CH₂OCH₃) N H F CO(CH₂OCH₃) N CH₃ FCO(CH₂OCH₃) CF H H CO(CH₂OCH₃) CF CH₃ H CO(CH₂OCH₃) CF H F CO(CH₂OCH₃)CF CH₃ F CO(CH₂OCH₃) CH H H CO(CH₂NMe₂) CH CH₃ H CO(CH₂NMe₂) CH H FCO(CH₂NMe₂) CH CH₃ F CO(CH₂NMe₂) N H H CO(CH₂NMe₂) N CH₃ H CO(CH₂NMe₂) NH F CO(CH₂NMe₂) N CH₃ F CO(CH₂NMe₂) CF H H CO(CH₂NMe₂) CF CH₃ HCO(CH₂NMe₂) CF H F CO(CH₂NMe₂) CF CH₃ F CO(CH₂NMe₂) CH H H CO₂CH₃ CH CH₃H CO₂CH₃ CH H F CO₂CH₃ CH CH₃ F CO₂CH₃ N H H CO₂CH₃ N CH₃ H CO₂CH₃ N H FCO₂CH₃ N CH₃ F CO₂CH₃ CF H H CO₂CH₃ CF CH₃ H CO₂CH₃ CF H F CO₂CH₃ CF CH₃F CO₂CH₃ CH H H CO₂CH₂CH₃ CH CH₃ H CO₂CH₂CH₃ CH H F CO₂CH₂CH₃ CH CH₃ FCO₂CH₂CH₃ N H H CO₂CH₂CH₃ N CH₃ H CO₂CH₂CH₃ N H F CO₂CH₂CH₃ N CH₃ FCO₂CH₂CH₃ CF H H CO₂CH₂CH₃ CF CH₃ H CO₂CH₂CH₃ CF H F CO₂CH₂CH₃ CF CH₃ FCO₂CH₂CH₃ CH H H Et CH CH₃ H Et CH H F Et CH CH₃ F Et N H H Et N CH₃ HEt N H F Et N CH₃ F Et CF H H Et CF CH₃ H Et CF H F Et CF CH₃ F Et; or

X Y Z R CH CH₃ F CH₃ CH H F CH₃ N H H CH₃ N CH₃ H CH₃ N H F CH₃ N CH₃ FCH₃ CF H H CH₃ CF CH₃ H CH₃ CF H F CH₃ CF CH₃ F CH₃ CH H H Ac CH CH₃ HAc CH H F Ac CH CH₃ F Ac N H H Ac N CH₃ H Ac N H F Ac N CH₃ F Ac CF H HAc CF CH₃ H Ac CF H F Ac CF CH₃ F Ac CH H H CO(CF₃) CH CH₃ H CO(CF₃) CHH F CO(CF₃) CH CH₃ F CO(CF₃) N H H CO(CF₃) N CH₃ H CO(CF₃) N H F CO(CF₃)N CH₃ F CO(CF₃) CF H H CO(CF₃) CF CH₃ H CO(CF₃) CF H F CO(CF₃) CF CH₃ FCO(CF₃) CH H H CO(CH₂CH₃) CH CH₃ H CO(CH₂CH₃) CH H F CO(CH₂CH₃) CH CH₃ FCO(CH₂CH₃) N H H CO(CH₂CH₃) N CH₃ H CO(CH₂CH₃) N H F CO(CH₂CH₃) N CH₃ FCO(CH₂CH₃) CF H H CO(CH₂CH₃) CF CH₃ H CO(CH₂CH₃) CF H F CO(CH₂CH₃) CFCH₃ F CO(CH₂CH₃) CH H H CO(NMe₂) CH CH₃ H CO(NMe₂) CH H F CO(NMe₂) CHCH₃ F CO(NMe₂) N H H CO(NMe₂) N CH₃ H CO(NMe₂) N H F CO(NMe₂) N CH₃ FCO(NMe₂) CF H H CO(NMe₂) CF CH₃ H CO(NMe₂) CF H F CO(NMe₂) CF CH₃ FCO(NMe₂) CH H H CO(iPr) CH CH₃ H CO(iPr) CH H F CO(iPr) CH CH₃ F CO(iPr)N H H CO(iPr) N CH₃ H CO(iPr) N H F CO(iPr) N CH₃ F CO(iPr) CF H HCO(iPr) CF CH₃ H CO(iPr) CF H F CO(iPr) CF CH₃ F CO(iPr) CH H HCO(CH₂OCH₃) CH CH₃ H CO(CH₂OCH₃) CH H F CO(CH₂OCH₃) CH CH₃ F CO(CH₂OCH₃)N H H CO(CH₂OCH₃) N CH₃ H CO(CH₂OCH₃) N H F CO(CH₂OCH₃) N CH₃ FCO(CH₂OCH₃) CF H H CO(CH₂OCH₃) CF CH₃ H CO(CH₂OCH₃) CF H F CO(CH₂OCH₃)CF CH₃ F CO(CH₂OCH₃) CH H H CO(CH₂NMe₂) CH CH₃ H CO(CH₂NMe₂) CH H FCO(CH₂NMe₂) CH CH₃ F CO(CH₂NMe₂) N H H CO(CH₂NMe₂) N CH₃ H CO(CH₂NMe₂) NH F CO(CH₂NMe₂) N CH₃ F CO(CH₂NMe₂) CF H H CO(CH₂NMe₂) CF CH₃ HCO(CH₂NMe₂) CF H F CO(CH₂NMe₂) CF CH₃ F CO(CH₂NMe₂) CH H H CO₂CH₃ CH CH₃H CO₂CH₃ CH H F CO₂CH₃ CH CH₃ F CO₂CH₃ N H H CO₂CH₃ N CH₃ H CO₂CH₃ N H FCO₂CH₃ N CH₃ F CO₂CH₃ CF H H CO₂CH₃ CF CH₃ H CO₂CH₃ CF H F CO₂CH₃ CF CH₃F CO₂CH₃ CH H H CO₂CH₂CH₃ CH CH₃ H CO₂CH₂CH₃ CH H F CO₂CH₂CH₃ CH CH₃ FCO₂CH₂CH₃ N H H CO₂CH₂CH₃ N CH₃ H CO₂CH₂CH₃ N H F CO₂CH₂CH₃ N CH₃ FCO₂CH₂CH₃ CF H H CO₂CH₂CH₃ CF CH₃ H CO₂CH₂CH₃ CF H F CO₂CH₂CH₃ CF CH₃ FCO₂CH₂CH₃ CH H H Et CH CH₃ H Et CH H F Et CH CH₃ F Et N H H Et N CH₃ HEt N H F Et N CH₃ F Et CF H H Et CF CH₃ H Et CF H F Et CF CH₃ F Et; or

X Y Z R CH CH₃ F CH₃ N H H CH₃ N CH₃ H CH₃ N H F CH₃ N CH₃ F CH₃ CF H HCH₃ CF CH₃ H CH₃ CF H F CH₃ CF CH₃ F CH₃ CH H H iPr CH CH₃ H Ac CH H FAc CH CH₃ F Ac N H H Ac N CH₃ H Ac N H F Ac N CH₃ F Ac CF H H Ac CF CH₃H Ac CF H F Ac CF CH₃ F Ac CH H H CO(CF₃) CH CH₃ H CO(CF₃) CH H FCO(CF₃) CH CH₃ F CO(CF₃) N H H CO(CF₃) N CH₃ H CO(CF₃) N H F CO(CF₃) NCH₃ F CO(CF₃) CF H H CO(CF₃) CF CH₃ H CO(CF₃) CF H F CO(CF₃) CF CH₃ FCO(CF₃) CH H H CO(CH₂CH₃) CH CH₃ H CO(CH₂CH₃) CH H F CO(CH₂CH₃) CH CH₃ FCO(CH₂CH₃) N H H CO(CH₂CH₃) N CH₃ H CO(CH₂CH₃) N H F CO(CH₂CH₃) N CH₃ FCO(CH₂CH₃) CF H H CO(CH₂CH₃) CF CH₃ H CO(CH₂CH₃) CF H F CO(CH₂CH₃) CFCH₃ F CO(CH₂CH₃) CH H H CO(NMe₂) CH CH₃ H CO(NMe₂) CH H F CO(NMe₂) CHCH₃ F CO(NMe₂) N H H CO(NMe₂) N CH₃ H CO(NMe₂) N H F CO(NMe₂) N CH₃ FCO(NMe₂) CF H H CO(NMe₂) CF CH₃ H CO(NMe₂) CF H F CO(NMe₂) CF CH₃ FCO(NMe₂) CH H H CO(iPr) CH CH₃ H CO(iPr) CH H F CO(iPr) CH CH₃ F CO(iPr)N H H CO(iPr) N CH₃ H CO(iPr) N H F CO(iPr) N CH₃ F CO(iPr) CF H HCO(iPr) CF CH₃ H CO(iPr) CF H F CO(iPr) CF CH₃ F CO(iPr) CH H HCO(CH₂OCH₃) CH CH₃ H CO(CH₂OCH₃) CH H F CO(CH₂OCH₃) CH CH₃ F CO(CH₂OCH₃)N H H CO(CH₂OCH₃) N CH₃ H CO(CH₂OCH₃) N H F CO(CH₂OCH₃) N CH₃ FCO(CH₂OCH₃) CF H H CO(CH₂OCH₃) CF CH₃ H CO(CH₂OCH₃) CF H F CO(CH₂OCH₃)CF CH₃ F CO(CH₂OCH₃) CH H H CO(CH₂NEt₂) CH CH₃ H CO(CH₂NMe₂) CH H FCO(CH₂NMe₂) CH CH₃ F CO(CH₂NMe₂) N H H CO(CH₂NMe₂) N CH₃ H CO(CH₂NMe₂) NH F CO(CH₂NMe₂) N CH₃ F CO(CH₂NMe₂) CF H H CO(CH₂NMe₂) CF CH₃ HCO(CH₂NMe₂) CF H F CO(CH₂NMe₂) CF CH₃ F CO(CH₂NMe₂) CH H H CO₂CH₃ CH CH₃H CO₂CH₃ CH H F CO₂CH₃ CH CH₃ F CO₂CH₃ N H H CO₂CH₃ N CH₃ H CO₂CH₃ N H FCO₂CH₃ N CH₃ F CO₂CH₃ CF H H CO₂CH₃ CF CH₃ H CO₂CH₃ CF H F CO₂CH₃ CF CH₃F CO₂CH₃ CH H H CO₂CH₂CH₃ CH CH₃ H CO₂CH₂CH₃ CH H F CO₂CH₂CH₃ CH CH₃ FCO₂CH₂CH₃ N H H CO₂CH₂CH₃ N CH₃ H CO₂CH₂CH₃ N H F CO₂CH₂CH₃ N CH₃ FCO₂CH₂CH₃ CF H H CO₂CH₂CH₃ CF CH₃ H CO₂CH₂CH₃ CF H F CO₂CH₂CH₃ CF CH₃ FCO₂CH₂CH₃ CH H H Et CH CH₃ H Et CH H F Et CH CH₃ F Et N H H Et N CH₃ HEt N H F Et N CH₃ F Et CF H H Et CF CH₃ H Et CF H F Et CF CH₃ F Et; or

X Y Z R CH CH₃ F CH₃ N H H CH₃ N CH₃ H CH₃ N H F CH₃ N CH₃ F CH₃ CF H HCH₃ CF CH₃ H CH₃ CF H F CH₃ CF CH₃ F CH₃ CH H H iPr CH CH₃ H Ac CH H FAc CH CH₃ F Ac N H H Ac N CH₃ H Ac N H F Ac N CH₃ F Ac CF H H Ac CF CH₃H Ac CF H F Ac CF CH₃ F Ac CH H H CO(CF₃) CH CH₃ H CO(CF₃) CH H FCO(CF₃) CH CH₃ F CO(CF₃) N H H CO(CF₃) N CH₃ H CO(CF₃) N H F CO(CF₃) NCH₃ F CO(CF₃) CF H H CO(CF₃) CF CH₃ H CO(CF₃) CF H F CO(CF₃) CF CH₃ FCO(CF₃) CH H H CO(CH₂CH₃) CH CH₃ H CO(CH₂CH₃) CH H F CO(CH₂CH₃) CH CH₃ FCO(CH₂CH₃) N H H CO(CH₂CH₃) N CH₃ H CO(CH₂CH₃) N H F CO(CH₂CH₃) N CH₃ FCO(CH₂CH₃) CF H H CO(CH₂CH₃) CF CH₃ H CO(CH₂CH₃) CF H F CO(CH₂CH₃) CFCH₃ F CO(CH₂CH₃) CH H H CO(NMe₂) CH CH₃ H CO(NMe₂) CH H F CO(NMe₂) CHCH₃ F CO(NMe₂) N H H CO(NMe₂) N CH₃ H CO(NMe₂) N H F CO(NMe₂) N CH₃ FCO(NMe₂) CF H H CO(NMe₂) CF CH₃ H CO(NMe₂) CF H F CO(NMe₂) CF CH₃ FCO(NMe₂) CH H H CO(iPr) CH CH₃ H CO(iPr) CH H F CO(iPr) CH CH₃ F CO(iPr)N H H CO(iPr) N CH₃ H CO(iPr) N H F CO(iPr) N CH₃ F CO(iPr) CF H HCO(iPr) CF CH₃ H CO(iPr) CF H F CO(iPr) CF CH₃ F CO(iPr) CH H HCO(CH₂OEt) CH CH₃ H CO(CH₂OCH₃) CH H F CO(CH₂OCH₃) CH CH₃ F CO(CH₂OCH₃)N H H CO(CH₂OCH₃) N CH₃ H CO(CH₂OCH₃) N H F CO(CH₂OCH₃) N CH₃ FCO(CH₂OCH₃) CF H H CO(CH₂OCH₃) CF CH₃ H CO(CH₂OCH₃) CF H F CO(CH₂OCH₃)CF CH₃ F CO(CH₂OCH₃) CH H H CO(CH₂NEt₂) CH CH₃ H CO(CH₂NMe₂) CH H FCO(CH₂NMe₂) CH CH₃ F CO(CH₂NMe₂) N H H CO(CH₂NMe₂) N CH₃ H CO(CH₂NMe₂) NH F CO(CH₂NMe₂) N CH₃ F CO(CH₂NMe₂) CF H H CO(CH₂NMe₂) CF CH₃ HCO(CH₂NMe₂) CF H F CO(CH₂NMe₂) CF CH₃ F CO(CH₂NMe₂) CH H H CO₂CH₃ CH CH₃H CO₂CH₃ CH H F CO₂CH₃ CH CH₃ F CO₂CH₃ N H H CO₂CH₃ N CH₃ H CO₂CH₃ N H FCO₂CH₃ N CH₃ F CO₂CH₃ CF H H CO₂CH₃ CF CH₃ H CO₂CH₃ CF H F CO₂CH₃ CF CH₃F CO₂CH₃ CH H H CO₂CH₂CH₃ CH CH₃ H CO₂CH₂CH₃ CH H F CO₂CH₂CH₃ CH CH₃ FCO₂CH₂CH₃ N H H CO₂CH₂CH₃ N CH₃ H CO₂CH₂CH₃ N H F CO₂CH₂CH₃ N CH₃ FCO₂CH₂CH₃ CF H H CO₂CH₂CH₃ CF CH₃ H CO₂CH₂CH₃ CF H F CO₂CH₂CH₃ CF CH₃ FCO₂CH₂CH₃ CH H H CH₂CH₂OCH₃ CH CH₃ H Et CH H F Et CH CH₃ F Et N H H Et NCH₃ H Et N H F Et N CH₃ F Et CF H H Et CF CH₃ H Et CF H F Et CF CH₃ FEt; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H H CF CH₃H CF H F CF CH₃ F; or

X Y Z CH Et H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H H CF CH₃H CF H F CF CH₃ F; or

X Y Z CH Et H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF H H CF CH₃H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F; or

X Y Z CH Et H CH CH₃ H CH H F CH CH₃ F N H H N CH₃ H N H F N CH₃ F CF HH CF CH₃ H CF H F CF CH₃ F;

or a pharmaceutically acceptable salt thereof.

The present invention includes a method of inhibiting protein kinaseactivity according to the present invention comprises administering acompound of Formula I, or a pharmaceutically acceptable salt thereof.The method includes wherein the protein kinase is IGF-IR. The methodincludes wherein the activity of the protein kinase affectshyperproliferative disorders. The method includes wherein the activityof the protein kinase influences angiogenesis, vascular permeability,immune response, cellular apoptosis, tumor growth, or inflammation.

A method of the present invention of treating a patient having acondition which is mediated by protein kinase activity, comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.The method includes wherein the protein kinase is IGF-IR. The methodincludes wherein the condition mediated by protein kinase activity is ahyperproliferative disorder. The method includes wherein the activity ofthe protein kinase influences angiogenesis, vascular permeability,immune response, cellular apoptosis, tumor growth, or inflammation. Themethod includes wherein the protein kinase is a protein serine/threoninekinase or a protein tyrosine kinase. The method includes wherein thecondition mediated by protein kinase activity is one or more ulcers. Themethod includes wherein the ulcer or ulcers are caused by a bacterial orfungal infection; or the ulcer or ulcers are Mooren ulcers; or the ulceror ulcers are a symptom of ulcerative colitis. The method includeswherein the condition mediated by protein kinase activity is Lymedisease, sepsis or infection by Herpes simplex, Herpes Zoster, humanimmunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis. Themethod includes wherein the condition mediated by protein kinaseactivity is von Hippel Lindau disease, pemphigoid, psoriasis, Paget'sdisease, or polycystic kidney disease. The method includes wherein thecondition mediated by protein kinase activity is fibrosis, sarcoidosis,cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendudisease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites,pleural effusions, pulmonary edema, cerebral edema or edema followingburns, trauma, radiation, stroke, hypoxia, or ischemia. The methodincludes wherein the condition mediated by protein kinase activity isovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, orendometriosis. The method includes wherein the condition mediated byprotein kinase-activity is chronic inflammation, systemic lupus,glomerulonephritis, synovitis, inflammatory bowel disease, Crohn'sdisease, glomerulonephritis, rheumatoid arthritis and osteoarthritis,multiple sclerosis, or graft rejection. The method includes wherein thecondition mediated by protein kinase activity is sickle cell anemia. Themethod includes wherein the condition mediated by protein kinaseactivity is an ocular condition. The method includes wherein the ocularcondition is ocular or macular edema, ocular neovascular disease,seleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits,chronic retinal detachment, post-laser treatment complications,conjunctivitis, Stargardt's disease, Eales disease, retinopathy, ormacular degeneration. The method includes wherein the condition mediatedby protein kinase activity is a cardiovascular condition. The methodincludes wherein the condition mediated by protein kinase activity isatherosclerosis, restenosis, ischemitheperfusion injury, vascularocclusion, venous malformation, or carotid obstructive disease. Themethod includes wherein the condition mediated by protein kinaseactivity is cancer. The method includes wherein the cancer is a solidtumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, arhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, anhematopoietic malignancy, or malignant ascites. The method includeswherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma,myeloma, or leukemia. Further, the method includes wherein the conditionmediated by protein kinase activity is Crow-Fukase (POEMS) syndrome or adiabetic condition. The method includes wherein the diabetic conditionis insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy,or microangiopathy. The method also includes wherein the protein kinaseactivity is involved in T cell activation, B cell activation, mast celldegranulation, monocyte activation, signal transduction, apoptosis, thepotentiation of an inflammatory response or a combination thereof.

The present invention includes the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the treatment of a disease which respondsto an inhibition of the IGF-IR-dependent cell proliferation.

The present invention includes the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the treatment of a disease which respondsto an inhibition of the IGF-IR tyrosine kinase.

The present invention includes a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. The invention includes a method of inhibitingprotein kinase activity that comprises administering such pharmaceuticalcomposition. The invention includes a method of treating a patienthaving a condition which is mediated by protein kinase activity byadministering to the patient a therapeutically effective amount of suchpharmaceutical composition.

The following include core structures of the present invention whereinat least one of X₃—X₇ is optionally substituted N and the core structurecan have Q¹ and R¹ substituents as defined above (the substituent ishydrogen where hydrogen is specified):

Name of unsubstituted Structure core with NH₂ group

1H-Pyrrolo[3,2- c]pyridin-4- ylamine

1H-Pyrrolo[2,3- c]pyridin-7- ylamine

2H-Pyrrolo[3,4- c]pyridin-4- ylamine

Pyrrolo[1,2-a]- pyrazin-1-ylamine

Pyrrolo[1,2-c]- pyrimidin-1- ylamine

7H-Pyrrolo[2,3- d]pyrimidin-4- ylamine

5H-Pyrrolo[3,2- d]pyrimidin-4- ylamine

6H-Pyrrolo[3,4- d]pyrimidin-4- ylamine

Pyrrolo[2,1-f]- [1,2,4]triazin-4- ylamine

Pyrrolo[1,2-a]- [1,3,5]triazin-4- ylamine

1H-Pyrrolo[2,3- d]pyridazin-4- ylamine

1H-Pyrrolo[2,3- d]pyridazin-7- ylamine

1-Methyl-6H- pyrrolo[3,4-d]- pyridazine

Pyrrolo[1,2-d]- [1,2,4]triazin-1- ylamine

Pyrrolo[1,2-d]- [1,2,4]triazin-4- ylamine

1H-Pyrazolo[4,3- c]pyridin-4- ylamine

1H-Pyrazolo[3,4- c]pyridin-7- ylamine

1H-Pyrazolo [4,3- d]pyrimidin-7- ylamine

1H-Pyrazolo[3,4- d]pyrimidin-4- ylamine

1H-Pyrazolo[3,4- d]pyridazin-7- ylamine

1H-Pyrazolo[3,4- d]pyridazin-4- ylamine

Imidazo[1,5-c]- pyrimidin-5- ylamine

Imidazo[1,5-d]- [1,2,4]triazin-4- ylamine

Imidazo[1,5-a]- [1,3,5]triazin-4- ylamine

Imidazo[1,5-a]- pyrazin-8-ylamine

Imidazo[1,5-d]- [1,2,4]triazin-1- ylamine

Imidazo[5,1-f]- [1,2,4]triazin-4- ylamine

The following include core structures of the present invention whereinR¹ is absent, at least one of X₃—X₇ is optionally substituted N and thecore structure can have Q¹ substituent as defined above (the substituentis hydrogen where hydrogen is specified):

Name of unsubstituted Structure core with NH₂ group

Pyrazolo[1,5-a]- pyrazin-4-ylamine

Pyrazolo[1,5-d]- [1,2,4]triazin-4- ylamine

1,5,7,7a-Tetraaza- inden-4-ylamine

3H-Imidazo[4,5-c]- pyridin-4-ylamine

3H-Imidazo[4,5-d]- pyridazin-4- ylamine

7H-Purin-6- ylamine

Imidazo[1,2-c]- pyrimidin-5- ylamine

Imidazo[1,2-d]- [1,2,4]triazin-5- ylamine

Imidazo[1,2-a]- [1,3,5]triazin-4- ylamine

3H-[1,2,3]- Triazolo[4,5-c]- pyridin-4-ylamine

3H-[1,2,3]- Triazolo[4,5-d]- pyridazin-4- ylamine

1H-[1,2,3]- Triazolo[4,5-d]- pyrimidin-7- ylamine

[1,2,3]Triazolo[1,5- a]pyrazin-4- ylamine

1,2,5,6,7a- Pentaazainden-4- ylamine

1,2,5,7,7a- Pentaazainden-4- ylamine

The compounds of the present invention include:

-   3-Cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinolin-2-yl]-phenylamine;-   1-(6-Chloro-2-phenylquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-phenoxyquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;-   [7-(8-Amino-3-cyclobutyl    imidazo[1,5-a]pyrazin-1-yl)-6-chloroquinolin-2-yl]-phenyl-amine;-   3-Cyclobutyl-1-(8-fluoro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(8-fluoro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-8-fluoroquinolin-2-yl]-phenyl-amine;-   3-Cyclobutyl-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-Cyclobutyl-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-4-methylquinolin-2-yl]-phenylamine;-   3-Cyclobutyl-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinolin-4-yl]-methylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-pyridin-2-ylquinolin-4-yl]methylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-thiophen-2-ylquinolin-4-yl]-methylamine;-   [7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenoxyquinolin-4-yl]-methylamine;-   7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-N⁴-methyl-N²-phenylquinoline-2,4-diamine;-   3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(6-chloro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(6-chloro-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(6-chloro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-4-methyl-2-thiophen-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-4-methyl-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-[8-Amino-1-(8-fluoro-4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(3-azetidin-1-ylmethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-quinolin-2-yl}-phenylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-pyridin-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-thiophen-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(3-azetidin-1-ylmethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-6-chloro-quinolin-2-yl}-phenylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(3-azetidin-1-ylmethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-4-methyl-quinolin-2-yl}-phenyl-amine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]quinolin-2-yl}-phenylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-phenylquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-phenoxyquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-6-chloroquinolin-2-yl}-phenylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-4-methylquinolin-2-yl}-phenylamine;-   3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   4-[8-Amino-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(6-chloro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(6-chloro-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(6-chloro-2-phenoxyquinolin-7-yl)-imidzo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(4-methyl-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[8-Amino-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[8-Amino-1-(2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[8-Amino-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   3-(4-Aminomethylcyclohexyl)-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(4-Aminomethylcyclohexyl)-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(4-Aminomethylcyclohexyl)-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   {7-[8-Amino-3-(4-aminomethylcyclohexyl)-imidazo[1,5-a]pyrazin-1-yl]-quinolin-2-yl}-phenylamine;-   7-Cyclobutyl-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-Cyclobutyl-5-(2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-Cyclobutyl-5-(2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   [7-(4-Amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-quinolin-2-yl]-phenylamine;-   7-Cyclobutyl-5-(2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   5-(6-Chloro-2-phenylquinolin-7-yl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   5-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   5-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   5-(6-Chloro-2-phenoxyquinolin-7-yl)-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   [7-(4-Amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-6-chloroquinolin-2-yl]-phenylamine;-   3-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-phenylaminoquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(6-chloro-2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(6-chloro-2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(6-chloro-2-phenylaminoquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(8-fluoro-2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(8-fluoro-2-phenylaminoquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(8-fluoro-2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanol;-   7-Cyclobutyl-5-(8-fluoro-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-Cyclobutyl-5-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-Cyclobutyl-5-(8-fluoro-2-thiophen-2-yl-quinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-Cyclobutyl-5-(8-fluoro-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   [7-(4-Amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-8-fluoroquinolin-2-yl]-phenylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-thiophen-2-yl-quinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]quinolin-2-yl}-phenylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(6-chloro-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(6-chloro-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-6-chloroquinolin-2-yl}-phenylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(8-fluoro-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-8-fluoroquinolin-2-yl}-phenyl-amine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(8-fluoro-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(4-methyl-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(4-methyl-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethyl    cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-4-methylquinolin-2-yl}-phenylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-phenylquinolin-4-yl}-methylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethyl    cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-pyridin-2-ylquinolin-4-yl}-methylamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-thiophen-2-ylquinolin-4-yl}-methylamine;-   7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]N⁴-methyl-N²-phenylquinoline-2,4-diamine;-   {7-[4-Amino-7-(3-azetidin-1-ylmethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-phenoxyquinolin-4-yl}-methylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   {7-[4-Amino-7-(3-dimethylaminomethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-quinolin-2-yl}-phenylamine;-   5-(6-Chloro-2-phenylquinolin-7-yl)-7-(3-dimethylaminomethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   5-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-7-(3-dimethylaminomethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   5-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-7-(3-dimethylaminomethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   {7-[4-Amino-7-(3-dimethylaminomethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-6-chloroquinolin-2-yl}-phenylamine;-   5-(6-Chloro-2-phenoxyquinolin-7-yl)-7-(3-dimethylaminomethylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(8-fluoro-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(8-fluoro-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(4-methyl-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(4-methyl-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   4-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(6-chloro-2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(6-chloro-2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(6-chloro-2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(6-chloro-2-phenoxyquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic    acid amide;-   7-(4-Aminomethylcyclohexyl)-5-(2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(6-chloro-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(6-chloro-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(4-methyl-2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(4-methyl-2-phenoxyquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(2-pyridin-2-yl-quinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(6-chloro-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(6-chloro-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(4-methyl-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(4-methyl-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(8-fluoro-2-thiophen-2-yl-quinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(8-fluoro-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(8-fluoro-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(4-Aminomethylcyclohexyl)-3-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   4-[4-Amino-3-(2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimi    din-1-yl]-cyclohexanecarboxylic acid amide;-   4-[4-Amino-3-(2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(6-chloro-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(6-chloro-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(8-fluoro-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(8-fluoro-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(4-methyl-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(4-methyl-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-3-(2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(6-chloro-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(6-chloro-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(8-fluoro-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(8-fluoro-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(4-methyl-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-3-(4-methyl-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexanecarboxylic    acid methylamide;-   1-Cyclobutyl-3-(2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-phenylquinolin-7-yl)-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-phenoxyquinolin-7-yl)-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(4-methyl-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-Cyclobutyl-3-(4-methyl-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-[4-Amino-3-(2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(6-chloro-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(6-chloro-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(4-methyl-2-phenylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   3-[4-Amino-3-(4-methyl-2-phenoxyquinolin-7-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclobutanol;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(6-chloro-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(6-chloro-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(4-methyl-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Azetidin-1-ylmethylcyclobutyl)-3-(4-methyl-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-phenylquinolin-7-yl)-1-(3-dimethylaminomethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-1-(3-dimethylaminomethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-phenoxyquinolin-7-yl)-1-(3-dimethylaminomethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-1-(3-dimethylaminomethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(4-methyl-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(4-methyl-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(8-fluoro-2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   1-(3-Dimethylaminomethylcyclobutyl)-3-(8-fluoro-2-phenoxyquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine;-   3-Cyclobutyl-1-(3-phenylquinoxalin-6-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-[8-Amino-1-(3-phenylquinoxalin-6-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(3-phenylquinoxalin-6-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   4-[8-Amino-1-(3-phenylquinoxalin-6-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(3-phenylquinoxalin-6-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[8-Amino-1-(2-phenylquinazolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   4-[8-Amino-1-(2-phenylquinazolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   3-Cyclobutyl-1-(2-phenylquinazolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-[8-Amino-1-(2-phenylquinazolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinazolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-[3-(2-Methoxyethoxy)-cyclobutyl]-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   1-(6-Chloro-2-phenylquinolin-7-yl)-3-[3-(2-methoxyethoxy)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine;-   3-[3-(2-Methoxyethoxy)-cyclobutyl]-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   1-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone;-   3-Bicyclo[3.1.0]hex-6-yl-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   6-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-bicyclo[3.1.0]hexan-3-ol;-   7-Cyclobutyl-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-Cyclobutyl-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-Cyclobutyl-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-Cyclobutyl-5-(2-pyridin-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   3-[4-Amino-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanol;-   3-[4-Amino-5-(2-pyridin-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanol;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-pyridin-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-pyridin-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Dimethylaminomethylcyclobutyl)-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   4-[4-Amino-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   4-[4-Amino-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   7-(4-Aminomethylcyclohexyl)-5-(2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(2-thiophen-2-ylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(2-phenoxyquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(4-Aminomethylcyclohexyl)-5-(6-chloro-2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   4-[4-Amino-5-(6-chloro-2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid amide;-   4-[4-Amino-5-(6-chloro-2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid methylamide;-   5-(6-Chloro-2-phenylquinolin-7-yl)-7-cyclobutylimidazo[5,1-f][1,2,4]triazin-4-ylamine;-   3-[4-Amino-5-(6-chloro-2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanol;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(6-chloro-2-phenylquinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine;-   7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-ylamine;-   3-[4-Amino-5-(2-phenylquinolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl]-cyclobutanol;-   7-Cyclobutyl-5-(2-phenylquinolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-ylamine;-   7-Phenyl-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;-   3-Isopropyl-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-tert-Butyl-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   5-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-pyrrolidin-3-ol;-   3-Cyclobutyl-1-(2-phenylquinolin-7-yl)-2H-imidazo[1,5-a]pyrazin-8-ylamine;-   trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid amide;-   trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methyl ester;-   trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid;-   trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic    acid methylamide;-   trans-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol;-   trans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione;-   trans-3-(4-Aminomethylcyclohexyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;-   3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;    and-   {3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol.

Unless otherwise stated, the connections of compound name moieties areat the rightmost recited moiety. That is, the substituent name startswith a terminal moiety, continues with any bridging moieties, and endswith the connecting moiety. For example, hetarylthioC₁₋₄alkyl has aheteroaryl group connected through a thio sulfur to a C₁₋₄ alkyl thatconnects to the chemical species bearing the substituent.

As used herein, for example, “C₀₋₄alkyl” is used to mean an alkyl having0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branchedconfiguration. An alkyl having no carbon is hydrogen when the alkyl is aterminal group. An alkyl having no carbon is a direct bond when thealkyl is a bridging (connecting) group. Further, C₀alkyl includes beinga substituted bond—that is, for example, —X—Y—Z is —C(O)—C₂₋₄alkyl whenX is C₀alkyl, Y is C₀alkyl, and Z is —C(O)—C₂₋₄alkyl.

In all embodiments of this invention, the term “alkyl” includes bothbranched and straight chain alkyl groups. Typical alkyl groups aremethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl,decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, andthe like.

The term “halo” refers to fluoro, chloro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl,trifluoromethyl, perfluoropropyl, 8-chlorononyl, and the like.

The term “acyl” refers to the structure —C(═O)—R, in which R is ageneral substituent variable such as, for example R¹ described above.Examples include, but are not limited to, (bi)(cyclo)alkylketo,(cyclo)alkenylketo, alkynylketo, arylketo, hetarylketo,heterocyclylketo, heterobicycloalkylketo, spiroalkylketo.

Unless otherwise specified, the term “cycloalkyl” refers to a 3-8 carboncyclic aliphatic ring structure, optionally substituted with forexample, alkyl, hydroxy, oxo, and halo, such as cyclopropyl,methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl,cyclohexyl, 4-chlorocyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “bicycloalkyl” refers to a structure consisting of twocycloalkyl moieties that have two or more atoms in common. If thecycloalkyl moieties have exactly two atoms in common they are said to be“fused”. Examples include, but are not limited to, bicyclo[3.1.0]hexyl,perhydronaphthyl, and the like. If the cycloalkyl moieties have morethan two atoms in common they are said to be “bridged”. Examplesinclude, but are not limited to, bicyclo[2.2.1]heptyl (“norbornyl”),bicyclo[2.2.2]octyl, and the like.

The term “spiroalkyl” refers to a structure consisting of two cycloalkylmoieties that have exactly one atom in common. Examples include, but arenot limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.

The term “heterobicycloalkyl” refers to a bicycloalkyl structure inwhich at least one carbon atom is replaced with a heteroatomindependently selected from oxygen, nitrogen, and sulfur.

The term “heterospiroalkyl” refers to a spiroalkyl structure in which atleast one carbon atom is replaced with a heteroatom independentlyselected from oxygen, nitrogen, and sulfur.

The term “alkylcarbonyloxyalkyl” refers to an ester moiety, for exampleacetoxymethyl, n-butyryloxyethyl, and the like.

The term “alkynylcarbonyl” refers to an alkynylketo functionality, forexample propynoyl and the like.

The term “hydroxyalkyl” refers to an alkyl group substituted with one ormore hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl, andthe like.

The term “alkylsulfonylalkyl” refers to an alkyl group substituted withan alkylsulfonyl, moiety, for example mesylmethyl,isopropylsulfonylethyl, and the like.

The term “alkylsulfonyl” refers to a sulfonyl moiety substituted with analkyl group, for example mesyl, n-propylsulfonyl, and the like.

The term “acetylaminoalkyl” refers to an alkyl group substituted with anamide moiety, for example acetylaminomethyl and the like.

The term “acetylaminoalkenyl” refers to an alkenyl group substitutedwith an amide moiety, for example 2-(acetylamino)vinyl and the like.

The term “alkenyl” refers to an ethylenically unsaturated hydrocarbongroup, straight or branched chain, having 1 or 2 ethylenic bonds, forexample vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl, andthe like.

The term “haloalkenyl” refers to an alkenyl group substituted with oneor more halo groups.

Unless otherwise specified, the term “cycloalkenyl” refers to a cyclicaliphatic 3 to 8 ring structure, optionally substituted with alkyl,hydroxy and halo, having 1 or 2 ethylenic bonds such asmethylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl,cyclohexenyl, 1,4-cyclohexadienyl, and the like.

The term “alkynyl” refers to an unsaturated hydrocarbon group, straightor branched, having at least one acetylenic bond, for example ethynyl,propargyl, and the like.

The term, “haloalkynyl” refers to an alkynyl group substituted with oneor more independent halo groups.

The term “alkylcarbonyl” refers to an alkylketo functionality, forexample acetyl, n-butyryl, and the like.

The term “alkenylcarbonyl” refers to an alkenylketo functionality, forexample, propenoyl and the like.

The term “aryl” refers to phenyl or naphthyl which may be optionallysubstituted. Examples of aryl include, but are not limited to, phenyl,4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3-nitrophenyl,2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,4-ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl,4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl,4-(trifluoromethyl)phenyl, and 2-iodo-4-methylphenyl.

The terms “heteroaryl” or “hetaryl” or “heteroar-” or “hetar-” refer toa substituted or unsubstituted 5- or 6-membered unsaturated ringcontaining one, two, three, or four independently selected heteroatoms,preferably one or two heteroatoms independently selected from oxygen,nitrogen, and sulfur or to a bicyclic unsaturated ring system containingup to 10 atoms including at least one heteroatom selected from oxygen,nitrogen, and sulfur. Examples of hetaryls include, but are not limitedto, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl,pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl,benzotriazolyl, benzofuranyl, and benzothienyl. The heterocyclic ringmay be optionally substituted with one or more substituents.

The terms “aryl-alkyl” or “arylalkyl” or “aralkyl” are used to describea group wherein the alkyl chain can be branched or straight chainforming a bridging portion with the terminal aryl, as defined above, ofthe aryl-alkyl moiety. Examples of aryl-alkyl groups include, but arenot limited to, optionally substituted benzyl, phenethyl, phenpropyl andphenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl,2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl,2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl,2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl,2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl,3-(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl,3-(4-(trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl,4-phenylbutyl, 4-(4-chlorophenyl)butyl, 4-(2-methylphenyl)butyl,4-(2,4-dichlorophenyl)butyl, 4-(2-methoxyphenyl)butyl, and10-phenyldecyl.

The terms “aryl-cycloalkyl” or “arylcycloalkyl” are used to describe agroup wherein the terminal aryl group is attached to a cycloalkyl group,for example phenylcyclopentyl and the like.

The terms “aryl-alkenyl” or “arylalkenyl” or “aralkenyl” are used todescribe a group wherein the alkenyl chain can be branched or straightchain forming a bridging portion of the aralkenyl moiety with theterminal aryl portion, as defined above, for example styryl(2-phenylvinyl), phenpropenyl, and the like.

The terms “aryl-alkynyl” or “arylalkynyl” or “aralkynyl” are used todescribe a group wherein the alkynyl chain can be branched or straightchain forming a bridging portion of the aryl-alkynyl moiety with theterminal aryl portion, as defined above, for example3-phenyl-1-propynyl, and the like.

The terms “aryl-oxy” or “aryloxy” or “aroxy” are used to describe aterminal aryl group attached to a bridging oxygen atom. Typical aryl-oxygroups include phenoxy, 3,4-dichlorophenoxy, and the like.

The terms “aryl-oxyalkyl” or “aryloxyalkyl” or “aroxyalkyl” are used todescribe a group wherein an alkyl group is substituted with a terminalaryl-oxy group, for example pentafluorophenoxymethyl and the like.

The term “heterocycloalkenyl” refers to a cycloalkenyl structure inwhich at least one carbon atom is replaced with a heteroatom selectedfrom oxygen, nitrogen, and sulfur.

The terms “hetaryl-oxy” or “heteroaryl-oxy” or “hetaryloxy” or“heteroaryloxy” or “hetaroxy” or “heteroaroxy” are used to describe aterminal hetaryl group attached to a bridging oxygen atom. Typicalhetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like.

The terms “hetarylalkyl” or “heteroarylalkyl” or “hetaryl-alkyl” or“heteroaryl-alkyl” or “hetaralkyl” or “heteroaralkyl” are used todescribe a group wherein the alkyl chain can be branched or straightchain forming a bridging portion of the heteroaralkyl moiety with theterminal heteroaryl portion, as defined above, for example3-furylmethyl, thenyl, furfuryl, and the like.

The terms “hetarylalkenyl” or “heteroarylalkenyl” or “hetaryl-alkenyl”or “heteroaryl-alkenyl” or “hetaralkenyl” or heteroaralkenyl” are usedto describe a group wherein the alkenyl chain can be branched orstraight chain forming a bridging portion of the heteroaralkenyl moietywith the terminal heteroaryl portion, as defined above, for example3-(4-pyridyl)-1-propenyl.

The terms “hetarylalkynyl” or “heteroarylalkynyl” or “hetaryl-alkynyl”or “heteroaryl-alkynyl” or “hetaralkynyl” or “heteroaralkynyl” are usedto describe a group wherein the alkynyl chain can be branched orstraight chain forming a bridging portion of the heteroaralkynyl moietywith the heteroaryl portion, as defined above, for example4-(2-thienyl)-1-butynyl.

The term “heterocyclyl” or “hetcyclyl” refers to a substituted orunsubstituted 4-, 5-, or 6-membered saturated or partially unsaturatedring containing one, two, or three heteroatoms, preferably one or twoheteroatoms independently selected from oxygen, nitrogen and sulfur; orto a bicyclic ring system containing up to 10 atoms including at leastone heteroatom independently selected from oxygen, nitrogen, and sulfurwherein the ring containing the heteroatom is saturated. Examples ofheterocyclyls include, but are not limited to, tetrahydrofuranyl,tetrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl,tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl,dioxanyl, indolinyl, and 5-methyl-6-chromanyl.

The terms “heterocyclylalkyl” or “heterocyclyl-alkyl” or“hetcyclylalkyl” or “hetcyclyl-alkyl” are used to describe a groupwherein the alkyl chain can be branched or straight chain forming abridging portion of the heterocyclylalkyl moiety with the terminalheterocyclyl portion, as defined above, for example 3-piperidinylmethyland the like.

The terms “heterocyclylalkenyl” or “heterocyclyl-alkenyl” or“hetcyclylalkenyl” or “hetcyclyl-alkenyl” are used to describe a groupwherein the alkenyl chain can be branched or straight chain forming abridging portion of the heterocyclylalkenyl moiety with the terminalheterocyclyl portion, as defined above, for example2-morpholinyl-1-propenyl and the like.

The terms “heterocyclylalkynyl” or “heterocyclyl-alkynyl” or“hetcyclylalkynyl” or “hetcyclyl-alkynyl” are used to describe a groupwherein the alkynyl chain can be branched or straight chain forming abridging portion of the heterocyclylalkynyl moiety with the terminalheterocyclyl portion, as defined above, for example2-pyrrolidinyl-1-butynyl and the like.

The term “carboxylalkyl” refers to a terminal carboxyl (—COOH) groupattached to branched or straight chain alkyl groups as defined above.

The term “carboxylalkenyl” refers to a terminal carboxyl (—COOH) groupattached to branched or straight chain alkenyl groups as defined above.

The term “carboxylalkynyl” refers to a terminal carboxyl (—COOH) groupattached to branched or straight chain alkynyl groups as defined above.

The term “carboxylcycloalkyl” refers to a terminal carboxyl (—COOH)group attached to a cyclic aliphatic ring structure as defined above.

The term “carboxylcycloalkenyl” refers to a terminal carboxyl (—COOH)group attached to a cyclic aliphatic ring structure having ethylenicbonds as defined above.

The terms “cycloalkylalkyl” or “cycloalkyl-alkyl” refer to a terminalcycloalkyl group as defined above attached to an alkyl group, forexample cyclopropylmethyl, cyclohexylethyl, and the like.

The terms “cycloalkylalkenyl” or “cycloalkyl-alkenyl” refer to aterminal cycloalkyl group as defined above attached to an alkenyl group,for example cyclohexylvinyl, cycloheptylallyl, and the like.

The terms “cycloalkylalkynyl” or “cycloalkyl-alkynyl” refer to aterminal cycloalkyl group as defined above attached to an alkynyl group,for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl, and the like.

The terms “cycloalkenylalkyl” or “cycloalkenyl-alkyl” refer to aterminal cycloalkenyl group as defined above attached to an alkyl group,for example 2-(cyclopenten-1-yl)ethyl and the like.

The terms “cycloalkenylalkenyl” or “cycloalkenyl-alkenyl” refer toterminal a cycloalkenyl group as defined above attached to an alkenylgroup, for example 1-(cyclohexen-3-yl)allyl and the like.

The terms “cycloalkenylalkynyl” or “cycloalkenyl-alkynyl” refer toterminal a cycloalkenyl group as defined above attached to an alkynylgroup, for example 1-(cyclohexen-3-yl)propargyl and the like.

The term “carboxylcycloalkylalkyl” refers to a terminal carboxyl (—COOH)group attached to the cycloalkyl ring portion of a cycloalkylalkyl groupas defined above.

The term “carboxylcycloalkylalkenyl” refers to a terminal carboxyl(—COOH) group attached to the cycloalkyl ring portion of acycloalkylalkenyl group as defined above.

The term “Carboxylcycloalkylalkynyl” refers to a terminal carboxyl(—COOH) group attached to the cycloalkyl ring portion of acycloalkylalkynyl group as defined above.

The term “carboxylcycloalkenylalkyl” refers to a terminal carboxyl(—COOH) group attached to the cycloalkenyl ring portion of acycloalkenylalkyl group as defined above.

The term “carboxylcycloalkenylalkenyl” refers to a terminal carboxyl(—COOH) group attached to the cycloalkenyl ring portion of acycloalkenylalkenyl group as defined above.

The term “carboxylcycloalkenylalkynyl” refers to a terminal carboxyl(—COOH) group attached to the cycloalkenyl ring portion of acycloalkenylalkynyl group as defined above.

The term “alkoxy” includes both branched and straight chain terminalalkyl groups attached to a bridging oxygen atom. Typical alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy and thelike.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halo groups, for example chloromethoxy, trifluoromethoxy,difluoromethoxy, perfluoroisobutoxy, and the like.

The term “alkoxyalkoxyalkyl” refers to an alkyl group substituted withan alkoxy moiety which is in turn is substituted with a second alkoxymoiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl, andthe like.

The term “alkylthio” includes both branched and straight chain alkylgroups attached to a bridging sulfur atom, for example methylthio andthe like.

The term “haloalkylthio” refers to an alkylthio group substituted withone or more halo groups, for example trifluoromethylthio and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group, for example isopropoxymethyl and the like.

The term “alkoxyalkenyl” refers to an alkenyl group substituted with analkoxy group, for example 3-methoxyallyl and the like.

The term “alkoxyalkynyl” refers to an alkynyl group substituted with analkoxy group, for example 3-methoxypropargyl.

The term “alkoxycarbonylalkyl” refers to a straight chain or branchedalkyl substituted with an alkoxycarbonyl, for exampleethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.

The term “alkoxycarbonylalkenyl” refers to a straight chain or branchedalkenyl as defined above substituted with an alkoxycarbonyl, for example4-(ethoxycarbonyl)-2-butenyl and the like.

The term “alkoxycarbonylalkynyl” refers to a straight chain or branchedalkynyl as defined above substituted with an alkoxycarbonyl, for example4-(ethoxycarbonyl)-2-butynyl and the like.

The term “haloalkoxyalkyl” refers to a straight chain or branched alkylas defined above substituted with a haloalkoxy, for example2-chloroethoxymethyl, trifluoromethoxymethyl and the like.

The term “haloalkoxyalkenyl” refers to a straight chain or branchedalkenyl as defined above substituted with a haloalkoxy, for example4-(chloromethoxy)-2-butenyl and the like.

The term “haloalkoxyalkynyl” refers to a straight chain or branchedalkynyl as defined above substituted with a haloalkoxy, for example4-(2-fluoroethoxy)-2-butynyl and the like.

The term “alkylthioalkyl” refers to a straight chain or branched alkylas defined above substituted with an alkylthio group, for examplemethylthiomethyl, 3-(isobutylthio)heptyl, and the like.

The term “alkylthioalkenyl” refers to a straight chain or branchedalkenyl as defined above substituted with an alkylthio group, forexample 4-(methylthio)-2-butenyl and the like.

The term “alkylthioalkynyl” refers to a straight chain or branchedalkynyl as defined above substituted with an alkylthio group, forexample 4-(ethylthio)-2-butynyl and the like.

The term “haloalkylthioalkyl” refers to a straight chain or branchedalkyl as defined above substituted with an haloalkylthio group, forexample 2-chloroethylthiomethyl, trifluoromethylthiomethyl and the like.

The term “haloalkylthioalkenyl” refers to a straight chain or branchedalkenyl as defined above substituted with an haloalkylthio group, forexample 4-(chloromethylthio)-2-butenyl and the like.

The term “haloalkylthioalkynyl” refers to a straight chain or branchedalkynyl as defined above substituted with a haloalkylthio group, forexample 4-(2-fluoroethylthio)-2-butynyl and the like.

The term “dialkoxyphosphorylalkyl” refers to two straight chain orbranched alkoxy groups as defined above attached to a pentavalentphosphorous atom, containing an oxo substituent, which is in turnattached to an alkyl, for example diethoxyphosphorylmethyl and the like.

One in the art understands that an “oxo” requires a second bond from theatom to which the oxo is attached. Accordingly, it is understood thatoxo cannot be substituted onto an aryl or heteroaryl ring.

The term “oligomer” refers to a low-molecular weight polymer, whosenumber average molecular weight is typically less than about 5000 g/mol,and whose degree of polymerization (average number of monomer units perchain) is greater than one and typically equal to or less than about 50.

Compounds described can contain one or more asymmetric centers and maythus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The invention also encompasses a pharmaceutical composition that iscomprised of a compound of Formula I in combination with apharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptablecarrier and a non-toxic therapeutically effective amount of a compoundof Formula I as described above (or a pharmaceutically acceptable saltthereof).

Moreover, within this preferred embodiment, the invention encompasses apharmaceutical composition for the treatment of disease by inhibitingkinases, comprising a pharmaceutically acceptable carrier and anon-toxic therapeutically effective amount of compound of Formula I asdescribed above (or a pharmaceutically acceptable salt thereof).

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium slats. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, formic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Preferred are citric, hydrobromic, formic, hydrochloric, maleic,phosphoric, sulfuric and tartaric acids. Particularly preferred areformic and hydrochloric acid.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or a pharmaceutically acceptable saltthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or a prodrug, or ametabolite, or a pharmaceutically acceptable salts thereof, of thisinvention can be combined as the active ingredient in intimate admixturewith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration. e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion, or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formula I, or a pharmaceutically acceptable saltthereof, may also be administered by controlled release means and/ordelivery devices. The compositions may be prepared by any of the methodsof pharmacy. In general, such methods include a step of bringing intoassociation the active ingredient with the carrier that constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound, or apharmaceutically acceptable salt, of Formula I. The compounds of FormulaI, or pharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration tohumans may contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

Generally, dosage levels on the order of from about 0.01 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, inflammation, cancer, psoriasis,allergy/asthma, disease and conditions of the immune system, disease andconditions of the central nervous system (CNS), may be effectivelytreated by the administration of from about 0.01 to 50 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

Biological Assays

The efficacy of the Examples of the invention, compounds of Formula I,as inhibitors of insulin-like growth factor-1 receptor (IGF-1R) weredemonstrated and confirmed by a number of pharmacological in vitroassays. The following assays and their respective methods can be carriedout with the compounds according to the invention. Activity possessed bycompounds of Formula I may be demonstrated in vivo.

In Vitro Tyrosine Kinase Assay

The IGF-1R inhibitory of a compound of Formula I can be shown in atyrosine kinase assay using purified GST fusion protein containing thecytoplasmic kinase domain of human IGF-1R expressed in Sf9 cells. Thisassay is carried out in a final volume of 90 μL containing 1-100 nM(depending on the specific activity) in an Immulon-4 96-well plate(Thermo Labsystems) pre-coated with 1 μg/well of substrate poly-glu-tyr(4:1 ratio) in kinase buffer (50 mM Hepes, pH 7.4, 125 mM NaCl, 24 mMMgCl₂, 1 mM MnCl₂, 1% glycerol, 200 μM Na₃VO₄, and 2 mM DTT). Theenzymatic reaction was initiated by addition of ATP at a finalconcentration of 100 μM. After incubation at rt for 30 min, the plateswere washed with 2 mM imidazole buffered saline with 0.02% Tween-20.Then the plate was incubated with anti-phosphotyrosine mouse monoclonalantibody pY-20 conjugated with horseradish peroxidase (HRP) (Calbiochem)at 167 ng/mL diluted in phosphate buffered saline (PBS) containing 3%bovine serum albumin (BSA), 0.5% Tween-20 and 200 μM Na₃VO₄ for 2 h atrt. Following 3×250 μL washes, the bound anti-phosphotyrosine antibodywas detected by incubation with 100 μL/well ABTS (Kirkegaard & PerryLabs, Inc.) for 30 min at rt. The reaction was stopped by the additionof 100 μL/well 1% SDS, and the phosphotyrosine dependent signal wasmeasured by a plate reader at 405/490 nm.

All EXAMPLES showed inhibition of IGF-1R. The following EXAMPLES showedefficacy and activity by inhibiting IGF-1R in the biochemical assay withIC₅₀ values less than 50 μM to less than 50 μM. Preferably the IC₅₀value is less than 5 μM. Advantageously, the IC₅₀ value is less than 1μM. More advantageously, the IC₅₀ value is less than 200 nM. Even moreadvantageously, the IC₅₀ value is less than 100 nM. Still moreadvantageously, the IC₅₀ value is less than 50 nM.

The most preferred EXAMPLES are selective towards IGF-1R.

Cell-based Autophosphotvrosine Assay

NIH 3T3 cells stably expressing full-length human IGF-1R were seeded at1×10⁴ cells/well in 0.1 mL Dulbecco's minimal essential medium (DMEM)supplemented with 10% fetal calf serum (FCS) per well in 96-well plates.On Day 2, the medium is replaced with starvation medium (DMEM containing0.5% FCS) for 2 h and a compound was diluted in 100% dimethyl sulfoxide(DMSO), added to the cells at six final concentrations in duplicates(20, 6.6, 2.2, 0.74, 0.25 and 0.082 μM), and incubated at 37° C. foradditional 2 h. Following addition of recombinant human IGF-1(100 ng/mL)at 37° C. for 15 min, the media was then removed and the cells werewashed once with PBS (phosphate-buffered saline), then lysed with coldTGH buffer (1% Triton-100, 10% glycerol, 50 mM HEPES [pH 7.4])supplemented with 150 mM NaCl, 1.5 mM MgCl, 1 mM EDTA and fresh proteaseand phosphatase inhibitors [10 μg/mL leupeptin, 25 μg/mL aprotinin, 1 mMphenyl methyl sulphonyl fluoride (PMSF), and 200 μM Na₃VO₄]. Celllysates were transferred to a 96-well microlite2 plate (Corning CoStar#3922) coated with 10 ng/well of IGF-1R antibody (Calbiochem, Cat#GR31L)and incubated at 4° C. overnight. Following washing with TGH buffer, theplate was incubated with anti-phosphotyrosine mouse monoclonal antibodypY-20 conjugated with horseradish peroxidase (HRP) for 2 h at rt. Theautophosphotyrosine was then detected by addition of Super Signal ELISAFemto Maximum Sensitivity Substrate (Pierce) and chemiluminescence wasread on a Wallac Victor² 1420 Multilabel Counter. The IC₅₀ curves of thecompounds were plotted using an ExcelFit program.

The preferred EXAMPLES showed inhibition of IGF-1R in the cell-basedassay. The following EXAMPLES showed efficacy and activity by inhibitingIGF-1R with IC₅₀ values less than 50 μM, with selectivity over insulinreceptor expected to be, but not limited to, in a range from 1-30 fold.Preferably the IC₅₀ value is less than 5 μM. More advantageously, theIC₅₀ value is less than 1 μM. Even more advantageously, the IC₅₀ valueis less than 200 nM. Ihsulin receptor autophosphotyrosine assays areperformed essentially as described above for IGF-1R cell-based assays,but use insulin (10 nM) as activating ligand and an insulin receptorantibody as capture antibody with HepG2 cells expressing endogenoushuman insulin receptor.

Compound of Formula I-AA is equal to compound of Formula I wherein X₁and X₂═CH, X₃ and X₅═N, and X₄, X₆, and X₇═C:

EXPERIMENTAL

In Scheme 1—Scheme 43 and the examples and intermediates to follow serveto demonstrate how to synthesize compounds of this invention, but in noway limit the invention. Additionally, the following abbreviations areused: Me for methyl, Et for ethyl, ^(i)Pr or ^(i)Pr for isopropyl, n-Bufor n-butyl, t-Bu for tert-butyl, Ac for acetyl, Ph for phenyl, 4Cl-Phor (4Cl)Ph for 4-chlorophenyl, 4Me-Ph or (4Me)Ph for 4-methylphenyl,(p-CH₃O)Ph for p-methoxyphenyl, (p-NO₂)Ph for p-nitrophenyl, 4Br-Ph or(4Br)Ph for 4-bromophenyl, 2-CF₃-Ph or (2CF₃)Ph for2-trifluoromethylphenyl, DMAP for 4-(dimethylamino)pyridine, DCC for1,3-dicyclohexylcarbodiimide, EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt for1-hydroxybenzotriazole, HOAt for 1-hydroxy-7-azabenzotriazole, TMP fortetramethylpiperidine, n-BuLi for n-butyllithium, CDI for1,1′-carbonyldiimidazole, DEAD for diethlyl azodicarboxylate, PS-PPh₃for polystyrene triphenylphosphine, DIEA for diisopropylethylamine, DIADfor diisopropyl azodicarboxylate, DBAD for di-tert-butylazodicarboxylate, HPFC for high performance flash chromatography, rt orRT for room temperature, min for minute, h for hour, Bn for benzyl, andLAH for lithium aluminum hydride.

Accordingly, the following are compounds which are useful asintermediates in the formation of IGF-1R inhibiting EXAMPLES.

The compounds of Formula I of this invention and the intermediates usedin the synthesis of the compounds of this invention were preparedaccording to the following methods. Method A was used when preparingcompounds of Formula I-AA as shown below in Scheme 1:

Method A:

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation of compounds of Formula I-AA, compound ofFormula II was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvents were isopropanol and a mixture of THFand isopropanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 80° C. and about 120° C. The above process toproduce compounds of the present invention was preferably carried in asealed reaction vessel such as but not limited to a thick walled glassreaction vessel or a stainless steel Parr bomb. An excess amount of thereactant, ammonia, was preferably used.

The compounds of Formula II of Scheme 1 were prepared as shown below inScheme 2.

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation of a compound of Formula II, an intermediate ofFormula III was treated with POCl₃ in a suitable solvent at a suitablereaction temperature. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; acetonitrile; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used or no solvent was used. The preferredsolvents included methylene chloride and acetonitrile. The above processwas carried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 20° C. and about 95° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III of Scheme 2 were prepared as shown below inScheme 3:

where Q¹ and R¹ are as defined previously for compound of Formula I andA¹=OH, alkoxy, or a leaving group such as chloro or imidazole.

In a typical preparation, of a compound of Formula III, a compound ofFormula IV and compound of Formula V were reacted under suitable amidecoupling conditions. Suitable conditions include but are not limited totreating compounds of Formula IV and V (when A¹=OH) with couplingreagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt and thelike. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride. Ifdesired, mixtures of these solvents were used, however the preferredsolvents were methylene chloride and DMF. The above process was carriedout at temperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about rt. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Alternatively, compounds of Formula IV and V (where A¹=F, Cl, Br, I)were reacted with bases such as triethylamine or ethyldiisopropylamineand the like in conjunction with DMAP and the like. Suitable solventsfor use in this process included, but were not limited to, ethers suchas tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such aschloroform or methylene chloride. If desired, mixtures of these solventswere used, however the preferred solvent was methylene chloride. Theabove process was carried out at temperatures between about −20° C. andabout 40° C. Preferably, the reaction was carried out between 0° C. and25° C. The above process to produce compounds of the present inventionwas preferably carried out at about atmospheric pressure although higheror lower pressures were used if desired. Substantially, equimolaramounts of compounds of Formula IV and V (where A¹=F, Cl, Br, I) andbase and substoichiometric amounts of DMAP were preferably used althoughhigher or lower amounts were used if desired. Additionally, othersuitable reaction conditions for the conversion of a compound of FormulaIV to a compound of Formula III can be found in Larock, R. C.Comprehensive Organic Transformations, 2^(nd) ed.; Wiley and Sons: NewYork, 1999, pp 1941-1949.

The compounds of Formula IV of Scheme 3 were prepared as shown below inScheme 4:

where Q¹ is as defined previously for compound of Formula I andA²=phthalimido or N³.

In a typical preparation, of a compound of Formula IV, a compound ofFormula VI is reacted under suitable reaction conditions in a suitablesolvent. When A²=phthalimido, suitable conditions include treatment ofcompound of Formula VI with hydrazine in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvent was ethanol. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired. In the transformation of compound of Formula VI to IV,if A²=N₃, then one skilled in the art would recognize that typical azidereduction conditions could be employed, including but not limited toPPh₃ and water or hydrogenation in the presence of a metal catalyst suchas palladium.

The compounds of Formula VI of Scheme 4 were prepared as shown below inScheme 5:

where Q¹ is as defined previously for compound of Formula I andA²=phthalimido or N³.

In a typical preparation of a compound of Formula VI (whenA²=phthalimido), a compound of Formula VII was reacted with aphthalimide under typical Mitsunobu conditions in a suitable solvent inthe presence of suitable reactants. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile (CH₃CN); chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent wasTHF. Suitable reactants for use in the above process included, but werenot limited to, triphenylphosphine and the like, and an azodicarboxylate(DIAD, DEAD, DBAD). The preferred reactants were triphenylphosphine orresin-bound triphenylphosphine (PS—PPh₃), and DIAD. The above processmay be carried out at temperatures between about −78° C. and about 100°C. Preferably, the reaction was carried out at about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Generally, one equivalent or a slight excess, 1.1equivalents, of triphenylphosphine, DIAD and phthalimide was used perequivalent of compound of Formula VII. Additionally, compound of FormulaVII can be reacted with Ts₂O, Ms₂O, Tf₂O, TsCl, MsCl, or SOCl₂ in whichthe hydroxy group is converted to a leaving group such as its respectivetosylate, mesylate, triflate, or halogen such as chloro and subsequentlyreacted with an amine equivalent such as NH(Boc)₂, phthalimide,potassium phthalimide, or sodium azide. Conversion of the amineequivalents by known methods such as by treating under acidic conditions(NH(Boc)₂), with hydrazine (phthalimide) as shown in Scheme 4, or withtriphenylphosphine/water (azide) will afford the desired amine as shownin Scheme 4.

The compounds of Formula VII of Scheme 5 were prepared from aldehydesQ¹-CHO and a 2-chloropyrazine VIII as shown below in Scheme 6:

where Q¹ is as defined previously for compound of Formula I.

In a typical preparation, of a compound of Formula VII, a compound ofFormula VIII was reacted under suitable reaction conditions in asuitable solvent with a compound of Formula Q¹-CHO. Suitable conditionsincluded but were not limited to treating compounds of Formula VIII witha base such as lithium tetramethylpiperidide (Li-TMP) followed bytreating with compounds of Formula Q¹-CHO. Lithium tetramethylpiperididemay be prepared by reacting tetramethylpiperidine with n-butyllithium at−78° C. and warming up to 0° C. Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like. Polar solvents such ashexamethylphosphoramide (HMPA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and the likemay be added if necessary. If desired, mixtures of these solvents wereused, however, the preferred solvent was THF. The above process may becarried out at temperatures between about −80° C. and about 20° C.Preferably, the reaction was carried out at −78° C. to 0° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula I of this invention and the intermediates usedin the synthesis of the compounds of this invention were preparedaccording to the following methods. Method AA was used when preparingcompounds of Formula I-AA from compound of Formula I-AAA as shown belowin Scheme 7:

Method AA:

where Q¹ and R¹ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I and B(OR)₂=suitable boronic acid/ester.

In a typical preparation of compounds of Formula I-AA, compound ofFormula I-AAA was reacted with a suitable boronic acid/ester (Q¹-B(OR)₂)in a suitable solvent via typical Suzuki coupling procedures. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, dioxane, dimethoxyethane,and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent wasdimethoxyethane/water. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 60° C. and about 100° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Substantially, equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of Formula I-AA from I-AAA. Forexample, compound of Formula I-AAA could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula I-AAA of Scheme 7 were prepared as shown belowin Scheme 8.

where R¹ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-AAA, compound ofFormula II-Z was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvents were isopropanol and a mixture of THFand isopropanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 80° C. and about 120° C. The above process toproduce compounds of the present invention was preferably carried in asealed reaction vessel such as but not limited to a thick walled glassreaction vessel or a stainless steel Parr bomb. An excess amount of thereactant, ammonia, was preferably used.

The compounds of Formula II-Z of Scheme 8 were prepared as shown belowin Scheme 9.

where R¹ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula II-Z, intermediateIII-Z was converted to compound of Formula II-Z′. Intermediate ofFormula III-Z was treated with POCl₃ in a suitable solvent at a suitablereaction temperature. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; acetonitrile; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used. The preferred solvents included methylenechloride and acetonitrile. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 20° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. In the conversion of compound of Formula III-Z toII-Z′, suitable halogenating agent were used, but were not limited to,Br₂, I₂, Cl₂, N-chlorosuccinimide, N-bromosuccinimide, orN-iodosuccinimide. The preferred halogenating agent wasN-iodosuccinimide. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent was DMF. Theabove process was carried out at temperatures between about −78° C. andabout 120° C. Preferably, the reaction was carried out between 40° C.and about 75° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantially,equimolar amounts of reactants were preferably used although higher orlower amounts were used if desired.

The compounds of Formula III-Z of Scheme 9 were prepared as shown belowin Scheme 10:

where R¹ is as defined previously for compound of Formula I and A′═OH,alkoxy, or a leaving group such as chloro or imidazole.

In a typical preparation, of a compound of Formula III-Z, a compound ofFormula IV-Z and compound of Formula V were reacted under suitable amidecoupling conditions. Suitable conditions include but are not limited totreating compounds of Formula IV-Z and V (when A¹=OH) with couplingreagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt and thelike. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride. Ifdesired, mixtures of these solvents were used, however the preferredsolvent was methylene chloride. The above process was carried out attemperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about 22° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Additionally, if compound of Formula IV-Z was a salt or bis-salt, asuitable base was required and included, but was not limited to,diisopropylethylamine or triethylamine. Alternatively, compounds ofFormula IV-Z and V (where A¹=F, Cl, Br, I) were reacted with bases suchas triethylamine or ethyldiisopropylamine and the like in conjunctionwith DMAP and the like. Suitable solvents for use in this processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; halogenated solvents such as chloroform or methylenechloride. If desired, mixtures of these solvents were used, however thepreferred solvent was methylene chloride. The above process was carriedout at temperatures between about −20° C. and about 40° C. Preferably,the reaction was carried out between 0° C. and 25° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially, equimolar amounts of compounds ofFormula IV-Z and V (where A¹=F, Cl, Br, I) and base andsubstoichiometric amounts of DMAP were preferably used although higheror lower amounts were used if desired. Additionally, other suitablereaction conditions for the conversion of an amine (compound of FormulaIV-Z) to an amide (compound of Formula III-Z) can be found in Larock, R.C. Comprehensive Organic Transformations, 2^(nd) ed.; Wiley and Sons:New York, 1999, pp 1941-1949.

The compounds of Formula IV-Z of Scheme 10 were prepared as shown belowin Scheme 11:

where A² is phthalimido or N³.

In a typical preparation, of a compound of Formula IV-Z, a compound ofFormula VI-Z is reacted under suitable reaction conditions in a suitablesolvent. When A²=phthalimido, suitable conditions include treatment ofcompound of Formula VI-Z with hydrazine in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvent was ethanol. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula VI-Z of Scheme 11 were prepared as shown belowin Scheme 12:

where A²=phthalimido or N³.

In a typical preparation of a compound of Formula VI-Z (whenA²=phthalimido), a compound of Formula VII-Z was reacted with aphthalimide under typical Mitsunobu conditions in a suitable solvent inthe presence of suitable reactants. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile (CH₃CN); chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent wasTHF. Suitable reactants for use in the above process included, but werenot limited to, triphenylphosphine and the like, and an azodicarboxylate(DIAD, DEAD, DBAD). The preferred reactants were triphenylphosphine orresin-bound triphenylphosphine (PS-PPh₃) and DIAD. The above process maybe carried out at temperatures between about −78° C. and about 100° C.Preferably, the reaction was carried out at about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Generally, 1.0 or 1.1 equivalents oftriphenylphosphine, DIAD and phthalimide was used per equivalent ofcompound of Formula VII-Z. Additionally, compound of Formula VII-Z canbe reacted with Ts₂O, Ms₂O, Tf₂O, TsCl, MsCl, or SOCl₂ in which thehydroxy group is converted to a leaving group such as its respectivetosylate, mesylate, triflate, or halogen such as chloro and subsequentlyreacted with an amine equivalent such as NH(Boc)₂, phthalimide,potassium phthalimide or sodium azide. Conversion of the amineequivalents by known methods such as by treating under acidic conditions(NH(Boc)₂), with hydrazine (phthalimide) as shown in Scheme 4, or withtriphenylphosphine/water (azide) will afford the desired amine as shownin Scheme 4.

The compounds of Formula VII-Z of Scheme 12 were prepared from2-chloropyrazine VIII as shown below in Scheme 13:

In a typical preparation, of a compound of Formula VII-Z, a compound ofFormula VIII was reacted under suitable reaction conditions in asuitable solvent. Suitable reaction conditions included, but were notlimited to, treating compounds of Formula VIII with a base such aslithium tetramethylpiperidide (Li-TMP) followed by treatment with areagent containing a carbonyl equivalent followed by treatment with asuitable reducing agent. Lithium tetramethylpiperidide may be preparedby reacting tetramethylpiperidine with n-butyllithium at −78° C. andwarming up to 0° C. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like. Polar solvents such as hexamethylphosphoramide(HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), andthe like may be added if necessary. If desired, mixtures of thesesolvents were used, however, the preferred solvent was THF. Suitablecarbonyl equivalent reagents include, but are not limited to, formamidessuch as DMF or suitable chloroformate such as methyl or ethylchloroformate. After addition of the suitable carbonyl equivalentreagent, the reaction if charged with a polar protic solvent such as,but not limited to, methanol or ethanol followed by treatment with asuitable reducing agent such as sodium borohydride. The above processmay be carried out at temperatures between about −80° C. and about 20°C. Preferably, the reaction was carried out at −78° C. to 0° C. Theabove process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula X-Z (Q¹-CHO) of Scheme 6 were prepared as shownbelow in Scheme 14:

where Q¹ is as defined previously for compound of Formula I.

In a typical preparation, of a compound of Formula X-Z (Q¹-CHO), acompound of Formula IX-Z (Q¹-CH₃) was reacted with a suitable oxidizingagent under suitable reaction conditions. Suitable oxidizing agentsincluded, but were not limited to, selenium dioxide. Suitable reactionconditions for use in the above process included, but were not limitedto, heating a mixture of selenium dioxide and compounds of Formula IX-Z(Q¹-CH₃) neat or in a suitable solvent such as, but not limited to,chlorobenzene or sulpholane. The above process may be carried out attemperatures between about 120° C. and about 180° C. Preferably, thereaction was carried out at 150° C. to 165° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Preferably, 1-1.5 equivalents of selenium dioxide were usedalthough higher or lower amounts were used if desired. Alternatively, acompound of Formula IX-Z (Q¹-CH₃) was reacted first with a halogenatingagent and a radical initiator under suitable reaction conditions in asuitable solvent to give a compound of Formula Q¹-CH₂—Hal (whereinHal=Cl or Br) that was then further reacted with DMSO and a base undersuitable reaction conditions to give a compound of Formula X-Z (Q¹CHO).Suitable halogenating agents included, but were not limited to, bromine,N-bromosuccinimide, and chlorine. Preferably, N-bromosuccinimide wasused. Suitable radical initiators included, but were not limited to,2,2′-azobisisobutyronitrile (AIBN) and UV light. Preferably, AIBN wasused. Preferably, carbon tetrachloride was used as solvent for thehalogenation step, although other halogenated solvents may be added. Thehalogenation may be carried out at temperatures between about 60° C. andabout 100° C. Preferably, the reaction was carried out at about 80° C.Suitable bases included, but were not limited to, sodiumhydrogencarbonate, sodium dihydrogenphosphate, disodiumhydrogenphosphate, and collidine. Preferably, sodium hydrogencarbonatewas used. DMSO was preferably used as solvent although other solventsmay be added. The second step may be carried out at temperatures betweenabout 40° C. and about 140° C. Preferably, the reaction was carried outat about 90° C. Additionally, other suitable reaction conditions for theconversion of Q¹-CH₃ to Q¹-CHO can be found in Larock, R. C.Comprehensive Organic Transformations, 2^(nd) ed.; Wiley and Sons: NewYork, 1999, pp 1205-1207 and 1222-1224.

The compounds of Formula IX-ZA (compound of Formula IX-Z wherein X₁₆=N,X₁₄ and X₁₅=C-E¹¹, and X₁₁—X₁₃=N or C-E¹¹) of Scheme 14 were prepared asshown below in Scheme 15:

where Hal=Cl, Br, or I; and E¹¹ and G¹ are as defined previously forcompound of Formula I.

In a typical preparation, of a compound of Formula IX-ZA, a compound ofFormula XI-Z was reacted first with an organolithium reagent Li-G¹ or aGrignard reagent Hal-Mg-G¹ in a suitable solvent to give a compound ofFormula XII-Z that was then further reacted with an oxidizing agent in asuitable solvent. Suitable solvents for use in the first step of aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like. If desired, mixtures ofthese solvents were used, however, the preferred solvent was THF. Theabove process may be carried out at temperatures between about −60° C.and about 66° C. Preferably, the reaction was carried out at about 0° C.to about 25° C. Suitable oxidizing agents included, but were not limitedto, air, sulfur, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).Preferred oxidizing agents were air and DDQ. Suitable solvents for thisprocess included, but were not limited to, esters such as ethyl acetate,ethers such as THF, aromatic solvents such as toluene. This process maybe carried out at temperatures between about 0° C. and the refluxtemperature of the solvent used. Preferably, the reaction was carriedout at about 20° C. to about 25° C. Alternatively, a compound of FormulaXII-Z or a mixture of compounds of Formula XII-Z and IX-ZA weresubjected directly to the process described in Scheme 14 to obtaincompounds of Formula X-Z (Q¹-CHO).

The compounds of Formula XIV-Z (Q¹-B(OR)₂) of Scheme 7 were prepared asshown below in Scheme 16:

where Q¹ is as defined previously for compound of Formula I, A¹¹¹=OTf orhalogen such as Cl, Br, or I and B(OR)₂=suitable boronic acid/ester.

In a typical preparation, of a compound of Formula XIV-Z (Q¹-B(OR)₂), acompound of Formula XIII-Z (Q¹-A¹¹¹) was reacted with a suitable metalcatalyst and a suitable boronating agent under suitable reactionconditions. Suitable metal catalyst agents included, but were notlimited to, Pd(OAc)₂ in the presence of1,3-bis(2,6-diisopropylphenyl)imidazolium chloride. Suitable boronatingagents included, but were not limited to, bis(pinacolato)diboron.Suitable reaction conditions for use in the above process included, butwere not limited to, heating a mixture of Pd(OAc)₂,1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, KOAc, andbis(pinacol)borane in a suitable solvent such as, but not limited to,THF. The above process may be carried out at temperatures between about20° C. and about 100° C. Preferably, the reaction was carried out at 60°C. to 80° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Preferably, 2-3equivalents of KOAc, 1-1.5 equivalents of bis(pinacol)borane, 0.03-1equivalent of Pd(OAc)₂, and 0.09-3 equivalents of1,3-bis(2,6-diisopropylphenyl)imidazolium chloride were used althoughhigher or lower amounts were used if desired. Additionally, othersuitable reaction conditions for the conversion of Q¹-A¹¹¹ to Q¹-B(OR)₂can be found in the literature which involve a variety of Q¹-A¹¹¹ oraryl/heteroarylhalides and a variety of conditions (Biooganic &Medicinal Chemistry Letters, 2003, 12(22), 4001; Biooganic & MedicinalChemistry Letters, 2003, 13(18), 3059; Chemical Communications(Cambridge, UK), 2003, 23, 2924; Synthesis, 2002, 17, 2503; AngewandteChemie, International Ed., 2002, 41(16), 3056; Journal of the AmericanChemical Society, 2002, 124(3), 390; Organic Letters, 2002, 4(4), 541;Tetrahedron, 2001, 57(49), 9813; Journal of Organic Chemistry, 2000,65(1), 164; Journal of Organic Chemistry, 1997, 62(19), 6458; Journal ofOrganometallic Chemistry, 1983, 259(3), 269). In some cases, compoundsof Formula XIII-Z (Q¹-A¹¹¹) and XIV-Z (Q¹-B(OR)₂) are commerciallyavailable or synthesized according to literature procedures. In caseswhere neither are available, compounds of Formula XIII-Z (Q¹-A¹¹¹) andXIV-Z (Q¹-B(OR)₂) were synthesized via procedures described in theexperimental section herein.

Both R¹ and Q¹ in the compounds described herein in some instancescontain functional groups which can be further manipulated. It would beappreciated by those skilled in the art that such manipulation offunctional groups can be accomplished with key intermediates or withlate stage compounds. Such functional group transformations areexemplified in the following Schemes 17-27 as well as in theexperimental section but are in no way meant to limit the scope of suchtransformations. Additionally, the chemistry shown in Schemes 17-27 canalso be applied to compounds of I-AAA, II-Z, and II-Z′.

The compounds of Formula I-A (compounds of Formula I-AA whereR¹=Z—CONR²R³) were prepared as shown below in Scheme 17:

where Q¹, R², and R³ are as defined previously for compound of Formula Iand A³=hydrogen or alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-A, when A³=alkyl andR² and R³ were both equal to H, reaction of compound of Formula II-A(compounds of Formula II where R¹=Z—CO₂A³) with ammonia in a suitablesolvent, afforded compound of Formula I-A. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvents were isopropanol and a mixture of isopropanol/THF. The aboveprocess was carried out at temperatures between about −78° C. and about120° C. Preferably, the reaction was carried out between 80° C. andabout 120° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantially,equimolar amounts of reactants were preferably used although higher orlower amounts were used if desired. Additionally, in a typicalpreparation of compound of Formula I-A, compound of Formula II-A (whenA³=H) was reacted with HNR²R³ followed by ammonia in a suitable solvent.When A³=H, typical coupling procedures as described in Scheme 3(conversion of CO₂H to COCl via treatment with SOCl₂ or oxalyl chloridefollowed by reaction with HNR²R³ or treatment of CO₂H and HNR²R³ withEDC or DCC in conjunction with DMAP, HOBT, or HOAt and the like) wereemployed to afford the transformation of a carboxylic acid to an amide.When A³=alkyl such as methyl or ethyl, treatment of the ester withAl(NR²R³) afforded conversion of CO₂A³ to CO(NR²R³). Subsequenttreatment with ammonia afforded compounds of Formula I-A.

The compounds of Formula I-A′ (compounds of Formula I-AA whereR¹=Z—CO₂A³) and I-A″ (compounds of Formula I-AA where R¹=Z—CO₂H) wereprepared as shown below in Scheme 18:

where Q¹ is as defined previously for compounds of Formula I andA³=alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-A′, compound ofFormula II-A was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 100° C. and about 120°C. The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. In most cases, the reactions wererun in a sealed tube. Substantially, equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.Typically, an excess of ammonia was used and the reaction was monitoredin order to ensure that additional of ammonia to the ester moiety didnot occur to an appreciable extent. Additionally, in a typicalpreparation of compound of Formula I-A″, compound of Formula I-A′ wasreacted under typical saponification conditions such as NaOH inTHF/H₂O/MeOH. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent was amixture of THF/H₂O/MeOH. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between rt and about 60° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially, equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.

The compounds of Formula II-B (compounds of Formula II where R¹=Z—CH₂OH)and I-B (compounds of Formula I-AA where R¹=Z—CH₂OH) were prepared asshown below in Scheme 19:

where Q¹ is as defined previously for compound of Formula I andA³=hydrogen or alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-B, compound of FormulaII-A is treated with a suitable reducing agent such as lithium aluminumhydride in a suitable solvent, such as THY to afford compound of FormulaII-B. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used.The preferred solvent was THF. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 0° C. and about 50° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Subsequent treatment of compound of Formula II-B underpreviously described ammonolysis conditions (ammonia in isopropanol in asealed tube at 120° C.), afforded compound of Formula I-B.

The compounds of Formula II-C (compounds of Formula II whereR¹=Z—CH₂A⁴), II-D (compounds of Formula II whereR¹=Z—CH₂A⁵(R²)(R³)_(d)), I-B (compounds of Formula I-AA whereR¹=Z—CH₂OH) and I-C (compounds of Formula I-AA whereR¹═Z—CH₂A⁵(R²)(R³)_(d)) were prepared as shown below in Scheme 20:

where Q¹, R², and R³ are as defined previously for compound of FormulaI; A⁴=suitable leaving group such as OTs, OMs, OTf, or halo such aschloro, bromo, or iodo; d=0 or 1; and A⁵=N, O or S.

In a typical preparation of compound of Formula I-C, the hydroxy groupof compound of Formula II-B was converted to a suitable leaving group,A⁴, such as Cl or OTs, OMs, or OTf, by reaction with SOCl₂ or Ts₂O,Ms₂O, or Tf₂O to afford compound of Formula II-C. Reaction of compoundof Formula II-C with HA⁵(R²)(R³)_(d) afforded compound of Formula II-D.Subsequent reaction of compound of Formula II-D under previouslydescribed ammonolysis conditions afforded compound of Formula I-C.Additionally, compound of Formula II-B was converted to compound ofFormula I-B as described previously in Scheme 19. Further conversion ofcompound of Formula I-B to compound of Formula I-C was accomplished byfollowing the previously described conditions for the conversion ofcompound of Formula II-B to compound of Formula II-C and the furtherconversion of compound of Formula II-C to compound of Formula II-D (inthe net conversion of OH to A⁵(R²)(R³)_(d)). Furthermore, compound ofFormula II-B can be directly converted to compound of Formula II-D bytreating compound of Formula II-B with various alkylating agent or withphenols via the Mitsunobu reaction to afford compounds Formula II-D(compounds of Formula II where R¹=CH₂—Z-A⁵(R²)(R³)_(d)) in which A⁵=O,d=0, and R²=alkyl or aryl).

The compounds of Formula I-C′ (compounds of Formula I-AA whereR¹=Z—CH₂-A²), I-C″ (compounds of Formula I-AA where R¹=Z—CH₂—NH₂), andI-C′″ (compounds of Formula I-AA where R¹=Z—CH₂—N(R²)(R³)) were−prepared as shown below in Scheme 21:

where Q¹, R², and R³ are as defined previously for compound of Formula Iand A²=phthalimido or N₃.

In a typical preparation of compounds of Formula I-C′, I-C″, and I-C′″,the hydroxy group of compound of Formula I-B was converted to A²,following the procedures as described in Scheme 5 for the conversion ofcompound of Formula VII to compound of Formula VI. Reaction of compoundof Formula I-C′ under conditions described in Scheme 4 afforded compoundof Formula I-C″. Reaction of compound of Formula I-C″ with, but notlimited to various alkylating agents, various aldehydes/ketones underreductive amination conditions, various acylating agents such as aceticanhydride, benzoyl chlorides, or with carboxylic acids in the presenceof EDC or DCC with HOBT or HOAT, or with sulphonylating agents such asTs₂O or MeSO₂Cl afforded compounds of Formula I-C′″. For example, in atypical preparation of compounds of Formula I-C′″, a compound of FormulaI-C″ is treated with a suitable acylating agent in the presence of asuitable base in a suitable solvent. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; and chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent waschloroform. Suitable bases for use in the above process included, butwere not limited to, trialkylamines such as diisopropylethylamine,triethylamine, or resin bound trialkylamines such as PS-DIEA. Thepreferred base was PS-DIEA. In the case where the suitable acylatingagent was acetic anhydride, the conversion of compound of Formula I-C″to compound of Formula I-C′″ where R²=H and R³=COCH₃ was accomplished.The above process was carried out at temperatures between about −78° C.and about 120° C. Preferably, the reaction was carried out between 0° C.and about 20° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantially,equimolar amounts of reactants were preferably used although higher orlower amounts were used if desired.

The compounds of Formula I-D (compounds of Formula I-AA whereR¹=(CH₂)_(n)—Z²—H and Z² is a heterocyclyl ring containing a nitrogenatom connected to H) and I-E (compounds of Formula I-AA whereR¹=(CH₂)_(n)—Z²—R² and Z² is a heterocyclyl ring containing a nitrogenatom connected to R²) were prepared as shown below in Scheme 22:

where Q¹ and R² are as defined previously for compound of Formula I,G^(99a) is C(═O)A⁶ or CO₂A⁶, n=0-5, and A⁶=alkyl, aryl, or aralkyl.

In a typical preparation of compound of Formula I-E, compound of FormulaII-E is treated with suitable reagents capable of converting N-G^(99a)to N—H and therefore afford compound of Formula I-D. For example,treatment of compound of Formula II-E (when G^(99a) is equal to CO₂Bn)under previously described ammonolysis conditions followed by treatmentwith concentrated HCl and a suitable basic workup, affords compound ofFormula I-D. Compound of Formula I-D can be subjected to variousconditions including but not limited to reductive aminations,alkylations and ar(hetar)ylations, and acylations to afford amides,ureas, guanidines, carbamates, thiocarbamates, sulphonamides, andvariously substituted nitrogen adducts to afford the net conversion ofNH to NR².

The compounds of Formula II-G (compounds of Formula II where R¹=Z³—OH),II-H (compounds of Formula II where R¹=Z-A⁵(R²)(R³)_(d)), I-F (compoundsof Formula I-AA where R¹=Z—OH), and I-G (compounds of Formula I-AA whereR¹=Z-A⁵(R²)(R³)_(d)) were prepared as shown below in Scheme 23:

where Q¹, R², and R³ are as defined previously for compound of FormulaI; d=0 or 1; and A⁵=N, O or S.

In a typical preparation of compound of Formula I-F and I-G, thefollowing transformations occurred: Compound of Formula II-F was reducedwith a suitable reducing agent in a suitable solvent, such as sodiumborohydride in methanol to afford compound of Formula II-G. Compound ofFormula II-G was subjected to previously described ammonolysisconditions to afford compound of Formula I-F. Additionally, compounds ofFormula II-F can be reacted with various amines under reductiveamination conditions (NaBH₃CN or NaBH(OAc)₃ with HA⁵(R²)(R³)_(d) whered=0, A⁵=N, and R² and R³ are as previously described for compound ofFormula I) to afford compounds of Formula II-H where d=0, A⁵=N, and R²and R³ are as previously described for compound of Formula I. Subsequentreaction of compounds of Formula II-H (compounds of Formula II whereR¹=Z-A⁵(R²)(R³)_(d) where d=0, A⁵=N, and R² and R³ are as previouslydescribed for compound of Formula I) with previously describedammonolysis conditions afforded compounds of Formula I-G. Furthermore,compounds of Formula II-H from II-G and I-G from I-F can be synthesizedaccording to the conditions described in Scheme 20 for thetransformations of II-B to II-D and I-B to I-C, respectively.

The compounds of Formula I-C′″ (compounds of Formula I-AA whereR¹=Z—CH₂—N(R²)(R³)) were prepared as shown below in Scheme 24:

where Q¹, R², and R³ are as defined previously for compound of Formula Iand A⁴=suitable leaving group such as Cl, OTs, OMs or OTf.

In a typical preparation of compound of Formula I-C′″ (compounds ofFormula I-AA where R¹=Z—CH₂—N(R²)(R³)), the following transformationsoccurred: Compounds of Formula II-J (compounds of Formula II whereR¹=Z═CH₂) were reacted with a suitable hydroborating agent such asdiborane, 9-borabicyclo[3.3.1]nonane (9-BBN), catecholborane and thelike, in a suitable solvent such as THF followed by treatment with ansuitable oxidizing agent such as hydrogen peroxide in basic aqueoussolution or NaBO₃.H₂O to afford compounds of Formula II-B. Furtherreaction of compounds of Formula II-B with previously describedammonolysis conditions afforded compounds of Formula I-B. The hydroxygroup of compounds of Formula I-B was then converted to a suitableleaving group, A⁴, such OTs, OMs, or OTf, by reaction with Ts₂O, Ms₂O,or Tf₂O, respectively, to afford compounds of Formula I-H. Furtherreaction of compounds of Formula I-H with HN(R²)(R³) where R² and R³ areas previously described for compounds of Formula I afforded compound ofFormula I-C′″ (compounds of Formula I-AA where R¹=Z—CH₂—N(R²)(R³)).

The compounds of Formula I-J (compounds of Formula I-AA whereR¹=Z—OH(CH₂OH)), I-K (compounds of Formula I-AA where R¹=Z═O), and I-L(compounds of Formula I-AA where R¹=Z—NR²R³) were prepared as shownbelow in Scheme 25:

where Q¹, R² and R³ are as defined previously for compound of Formula I.

In a typical preparation of compound of Formula I-J (compounds ofFormula I-AA where R¹=Z—OH(CH₂OH)), I-K (compounds of Formula I-AA whereR¹=Z═O), and I-L (compounds of Formula I-AA where R¹=Z—NR²R³) compoundof Formula II-J was treated under (compounds of Formula II whereR¹=Z═CH₂) was reacted with a suitable dihydroxylating agent such asosmium tetraoxide in the presence of NMO in a suitable solvent such asTHF to afford compound of Formula II-K (compounds of Formula II whereR¹=Z—OH(CH₂OH)) as a mixture of cis and trans isomers. Compounds ofFormula II-K (compounds of Formula II where R¹=Z—OH(CH₂OH)) were treatedwith a suitable oxidizing agent, such as but not limited to, NaIO₄,converting the diol into a ketone moiety, affording compound of FormulaII-L (compounds of Formula II where R¹=Z═O). Compound of Formula II-L(compounds of Formula II where R¹=Z═O) was then treated under typicalreductive amination conditions, involving a suitable amine, HNR²R³ and asuitable reducing agent, such as but not limited to, NaBH(OAc)₃ orNaBH(CN)₃, affording compound of Formula II-M (compounds of Formula IIwhere R¹=Z—NR²R³). Compound of Formula II-M (compounds of Formula IIwhere R¹=Z—NR²R³) was treated under ammonolysis conditions, ammonia inisopropanol in a stainless steel bomb at 110° C., to afford compound ofFormula I-L (compounds of Formula I-AA where R¹=Z—NR²R³). Moreover,compound of Formula II-K (compounds of Formula II where R¹=Z—OH(CH₂OH))was treated under the ammonolysis conditions described above to affordcompound of Formula I-J (compounds of Formula I-AA where R¹=Z—OH(CH₂OH))as a mixture of isomers. Compound of Formula I-J (compounds of FormulaI-AA where R¹=Z—OH(CH₂OH)) was treated with a suitable oxidizing agent,such as but not limited to, NaIO₄, converting the diol into a ketonemoiety, affording compound of Formula I-K (compounds of Formula I-AAwhere R¹=Z═O), which was treated under the typical reductive aminationconditions described above to afford compound of Formula I-L (compoundsof Formula I-AA where R¹=Z—NR²R³).

The compounds of Formula I-N (compounds of Formula I-AA whereR¹=Z—OH(CH₂NR²R³)) were prepared as shown below in Scheme 26:

where Q¹, R², and R³ are as defined previously for compound of FormulaI; A⁴=suitable leaving group such as OTs, OMs, or OTf.

In a typical preparation of compounds of Formula I-N (compounds ofFormula I-AA where R¹=Z—OH(CH₂NR²R³)), the primary hydroxyl group ofcompound of Formula I-J (compounds of Formula I-AA where R¹=Z—OH(CH₂OH))was converted to a suitable leaving group, A⁴, such as OTs, OMs, or OTf,by reaction with Ts₂O, Ms₂O, or Tf₂O in the presence of a suitable basesuch as diisopropylamine or pyridine and solvent such as THF ormethylene chloride to afford compound of Formula I-M (compounds ofFormula I-AA where R¹=Z—OH(CH₂A⁴)). Reaction of compound of Formula I-M(compounds of Formula I-AA where R¹=Z—OH(CH₂A⁴)) with HN(R²)(R³) in asuitable solvent such as THF or methylene chloride afforded compound ofFormula I-N (compounds of Formula I where R¹=Z—OH(CH₂NR²R³)).

The compounds of Formula I-O (compounds of Formula I whereR¹=Z³—OH(G¹¹)) were prepared as shown below in Scheme 27:

where Q¹ and G¹¹ are as defined previously for compound of Formula I.

In a typical preparation of compounds of Formula I-O (compounds ofFormula I where R¹=Z—OH(G¹¹)), the ketone moiety of compound of FormulaII-L (compounds of Formula II where R¹=Z═O) was reacted with a suitablenucleophilic reagent such as MeMgBr or MeLi in a suitable solvent suchas THF to afford compound of Formula II-N (compounds of Formula II whereR¹=Z—OH(G¹¹)). Compound of Formula II-N (compounds of Formula II whereR¹=Z—OH(G¹¹)) was reacted under ammonolysis conditions, ammonia inisopropanol in a stainless steel bomb at 110° C., to afford compound ofFormula I-O (compounds of Formula I where R¹=Z—OH(G¹¹)). Additionally,compound of Formula I-O (compounds of Formula I where R¹=Z—OH(G¹¹)) wasprepared by reacting compound of Formula I-K (compounds of Formula I-AAwhere R¹=Z—O) with a suitable nucleophilic reagent such as MeMgBr orMeLi in a suitable solvent such as THF.

Compound of Formula I-AB is equal to compound of Formula I whereinX₁=CH, X₂, X₄ and X₅=N, and X₃, X₆ and X₇=C; Q¹ is as defined for acompound of Formula I; R¹ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl,bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents; and G¹¹ is as defined for a compound of Formula I:

Method AB was used when preparing compounds of Formula I-AB as shownbelow in Scheme 28:

Method AB:

where Q¹ and R¹ are as defined previously for compound of Formula I-AB,A¹¹=halogen such as Cl, Br, or I, and Q¹-B(OR)₂=suitable boronicacid/ester.

In a typical preparation of compounds of Formula I-AB, compound ofFormula I-ABA was reacted with a suitable boronic acid/ester of FormulaXIV-Z (Q¹-B(OR)₂) in a suitable solvent via typical Suzuki couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent systems wereTHF/water and DMF/water. The above process was carried out attemperatures between about 20° C. and about 120° C. Preferably, thereaction was carried out between 80° C. and about 100° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of Formula I-AB from I-ABA. Forexample, compound of Formula I-ABA could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula I-ABA wherein R¹ is C₁₋₁₀alkyl,cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents, of Scheme 28 were prepared as shown below in Scheme 29:

where R¹ is C₁₋₁₀alkyl, cycloC₃₋₄₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; G¹¹ is as defined previously for compoundof Formula I, and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula I-ABA, a compound ofFormula I-ABB was reacted with an alcohol R¹—OH under typical Mitsunobuconditions in a suitable solvent in the presence of suitable reactants.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was THF. Suitable reactants for use inthe above process included, but were not limited to, triphenylphosphineand the like, and an azodicarboxylate (DIAD, DEAD, DBAD). The preferredreactants were triphenylphosphine or resin-bound triphenylphosphine andDIAD. The above process may be carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction was carried outbetween about 0° C. and 25° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially, equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Generally, oneequivalent of triphenylphosphine, DIAD, and R¹—OH was used perequivalent of compound of Formula I-ABB.

Alternatively, the compounds of Formula I-ABA may be prepared byalkylating compounds of Formula I-ABB with an alkylating agent R¹-LG,wherein LG is a leaving group including, but not limited to, chloride,bromide, iodide, tosylate, mesylate, trifluoromethanesulfonate, undertypical alkylation conditions known to someone skilled in the art.

Preferably, in compounds of Formula I-ABB, A¹¹=Br and I. These compoundsare known (A¹¹=I: H. B. Cottam et al., J. Med. Chem. 1993, 36 (22),3424-3430; A¹¹=Br: T. S. Leonova et al., Khim. Geterotsikl. Soedin.1982, (7), 982-984).

Compound of Formula I-AC is equal to compound of Formula I wherein X₁and X₅=CH, X₂ and X₄=N, and X₃, X₆ and X₇=C; Q¹ is as defined for acompound of Formula I; R¹ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl,bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents; and G¹¹ is as defined for a compound of Formula I:

Method AC was used when preparing compounds of Formula I-AB as shownbelow in Scheme 30:

Method AC:

where Q¹ and R¹ are as defined previously for compound of Formula I-AC,A¹¹=halogen such as Cl, Br, or I and Q¹-B(OR)₂=suitable boronicacid/ester.

In a typical preparation of compounds of Formula I-AC, compound ofFormula I-ACA was reacted with a suitable boronic acid/ester XIV-Z(Q¹-B(OR)₂) in a suitable solvent via typical Suzuki couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent systems wereTHF/water and DMF/water. The above process was carried out attemperatures between about 20° C. and about 120° C. Preferably, thereaction was carried out between 80° C. and about 100° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of formula I-AC from I-ACA. Forexample, compound of Formula I-ACA could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula I-ACA of Scheme 30 were prepared as shown belowin Scheme 31:

where R¹ is as defined previously for compound of Formula I-AC, andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-ACA, compound ofFormula XV was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 80° C. and about 100°C. The above process to produce compounds of the present invention waspreferably carried out in a glass pressure tube or a stainless steelreactor. Preferably, an excess of ammonia was used.

The compounds of Formula XVA (=compounds of Formula XV of Scheme 31wherein R¹ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents) were prepared as shown below in Scheme 32:

where R¹ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; G¹¹ is as defined previously for compoundof Formula I; and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula XVA, a compound ofFormula XVI was reacted with an alcohol R¹—OH under typical Mitsunobuconditions in a suitable solvent in the presence of suitable reactants.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was THF. Suitable reactants for use inthe above process included, but were not limited to, triphenylphosphineand the like, and an azodicarboxylate (DIAD, DEAD, DBAD). The preferredreactants were triphenylphosphine or resin-bound triphenylphosphine andDIAD. The above process may be carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction was carried outbetween about 0° C. and 25° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially, equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Generally, oneequivalent of triphenylphosphine, DIAD, and R¹—OH was used perequivalent of compound of Formula XVI.

Alternatively, the compounds of Formula XVA may be prepared byalkylating compounds of Formula XVI with an alkylating agent R¹-LG,wherein LG is a leaving group including, but not limited to, chloride,bromide, iodide, tosylate, mesylate, trifluoromethanesulfonate, undertypical alkylation conditions known to someone skilled in the art.

The compounds of Formula XVB (=compounds of Formula XV of Scheme 31wherein R¹ is aryl or heteroaryl, optionally substituted by one or moreindependent G¹¹ substituents) were prepared as shown below in Scheme 33:

where R¹ is aryl or heteroaryl, optionally substituted by one or moreindependent G¹¹ substituents, G¹¹ is as defined previously for compoundof Formula I; and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula XVB, compound ofFormula XVI was reacted with a suitable boronic acid of FormulaR¹—B(OH)₂ in a suitable solvent via typical copper(II)-mediated couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme,1,4-dioxane, and the like; dimethylformamide (DMF);N-methylpyrrolidinone (NMP); chlorinated solvents such as methylenechloride (CH₂Cl₂). If desired, mixtures of these solvents were used,however, the preferred solvent was methylene chloride (CH₂Cl₂). Suitablereactants for use in the above process included, but were not limitedto, copper(H) acetate (Cu(OAc)₂), copper(H) triflate (Cu(OTf)₂), and thelike, and a base (pyridine, and the like). The preferred reactants wereCu(OAc)₂ and pyridine. The above process to produce compounds of thepresent invention was preferably carried out at about atmosphericpressure under air, although higher or lower pressures could be used ifdesired. Preferably, the reaction was carried out at about 22° C.Generally, 1.5 eq. of copper(II) acetate, 2 eq. of pyridine, and 2 eq.of boronic acid of Formula R¹—B(OH)₂ were used per equivalent ofcompound of Formula XVI.

All compounds of Formula XVI are known in the literature (A¹¹=I: L. B.Townsend et al., J. Med. Chem. 1990, 33, 1984-92; A¹¹=Br, Cl: L. B.Townsend et al., J. Med. Chem. 1988, 31, 2086-2092). Preferably, A¹¹=Brand I.

Both R¹ and Q¹ in the compounds described herein in some instancescontain functional groups that can be further manipulated. It would beappreciated by those skilled in the art that such manipulation offunctional groups can be accomplished with key intermediates or withlate stage compounds. Such functional group transformations areexemplified in the following Schemes 34-35 as well as in theexperimental section but are in no way meant to limit the scope of suchtransformations.

The compounds of Formula I-ACA′ (=compounds of Formula I-ACA whereR¹=Z—CONR²R³) were prepared from compounds of Formula XV′ (=compounds ofFormula XV where R¹=Z—CO₂A³) as shown below in Scheme 34:

where R² and R³ are as defined previously for compound of Formula I;A¹¹=halogen such as Cl, Br, or I; and A³=hydrogen or alkyl such asmethyl or ethyl.

In a typical preparation of compound of Formula I-ACA′, when A³=alkyland R² and R³ were both equal to H, reaction of compound of Formula XV′with ammonia in a suitable solvent, afforded compound of Formula I-ACA′.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 80° C. and about 100°C. The above process to produce compounds of the present invention waspreferably carried out in a glass pressure tube or a stainless steelreactor. Preferably, an excess of ammonia was used. Additionally, in atypical preparation of compound of Formula I-ACA′ (compounds of FormulaI-ACA where R¹=Z—CONR²R³), compound of Formula XV′ (compounds of FormulaXV′ where R¹=Z—CO₂A³) was reacted with HNR²R³ followed by ammonia in asuitable solvent. When A³=H, typical coupling procedures (such asconversion of —CO₂H to —COCl via treatment with SOCl₂ or oxalyl chloridefollowed by reaction with HNR²R³ or treatment of —CO₂H and HNR²R³ withEDC or DCC in conjunction with DMAP, HOBT, or HOAt and the like) wereemployed to afford the transformation of a carboxylic acid to an amide.When A³=alkyl such as methyl or ethyl, treatment of the ester withAl(NR²R³) afforded conversion of —CO₂A³ to —CO(NR²R³). Subsequenttreatment with ammonia afforded compounds of Formula I-ACA′.

The chemistry shown in Scheme 34 can also be applied to compounds withQ¹ in place of A¹¹.

The compounds of Formula XVIII (compounds of Formula XV, I-ACA, or I-ACwhere R¹=Z—CH₂OH), XIX (compounds of Formula XV, I-ACA, or I-AC whereR¹=Z—CH₂LG), and XX (compounds of Formula XV, I-ACA, or I-AC whereR¹=Z—CH₂A⁵(R²)(R³)_(d)) were prepared as shown below in Scheme 35:

where Q¹, R², and R³ are as defined previously for compound of FormulaI; LG=suitable leaving group such as tosylate, mesylate,trifluoromethanesulfonate, or halo such as chloro, bromo, or iodo; d=0or 1; A³=hydrogen or alkyl such as methyl or ethyl; A¹¹=halogen such asCl, Br, or I; A¹²=Cl or NH₂; A¹³=A¹¹or Q¹; and A⁵=N, O or S.

The following table indicates the relations between the compounds ofFormulas XVII-XX, A¹², A¹³, compounds of Formulas I-AC, I-ACA, and XV,and R¹.

Compound of . . . is equal to Formula . . . wherein A¹² = and A¹³ =Formula . . . wherein R¹ = XVII Cl A¹¹ XV Z—CO₂A³ XVII NH₂ A¹¹ I-ACAZ—CO₂A³ XVII NH₂ Q¹ I-AC Z—CO₂A³ XVIII Cl A¹¹ XV Z—CH₂OH XVIII NH₂ A¹¹I-ACA Z—CH₂OH XVIII NH₂ Q¹ I-AC Z—CH₂OH XIX Cl A¹¹ XV Z—CH₂LG XIX NH₂A¹¹ I-ACA Z—CH₂LG XIX NH₂ Q¹ I-AC Z—CH₂LG XX Cl A¹¹ XV Z—CH₂A⁵R²(R³)_(d)XX NH₂ A¹¹ I-ACA Z—CH₂A⁵R²(R³)_(d) XX NH₂ Q¹ I-AC Z—CH₂A⁵R²(R³)_(d)

In a typical preparation of compound of Formula XVIII (compounds ofFormula XV, I-ACA, or I-AC, where R¹=Z—CH₂OH), compound of Formula XVII(compounds of Formula XV, I-ACA, or I-AC, where R¹=Z—CO₂A³) is treatedwith a suitable reducing agent, such as lithium aluminum hydride ordiisobutylaluminum hydride, in a suitable solvent, such as THF ormethylene chloride, to afford compound of Formula XVIII. In a typicalpreparation of compound of Formula XX (compounds of Formula XV, I-ACA,or I-AC, where R¹=Z—CH₂A⁵(R²)(R³)_(d)), the hydroxy group of compound ofFormula XVIII was converted to a suitable leaving group, LG, such as Clor tosylate, mesylate, or triflate, by reaction with SOCl₂ or Ts₂O,Ms₂O, or Tf₂O to afford compound of Formula XIX (compounds of FormulaXV, I-ACA, or I-AC, where R¹=Z—CH₂LG). Reaction of compound of FormulaXIX with HA⁵(R²)(R³)_(d) afforded compound of Formula XX. Furthermore,compound of Formula XVIII can be directly converted to compound ofFormula XX by treating compound of Formula XVIII with various alkylatingagents or under typical Mitsunobu reaction conditions to affordcompounds of Formula XX (compounds of Formula XV, I-ACA, or I-AC, whereR¹=Z—CH₂A⁵(R²)(R³)_(d)) in which A⁵ 32 O, d=0, and R²=alkyl or aryl).Someone skilled in the art will choose the most appropriate stage duringthe sequence shown in Scheme 35 to convert A¹²=Cl to A¹²=NH₂ asdescribed in Scheme 31, and to convert A¹³=A¹¹ to A¹³=Q¹ as described inScheme 30, if applicable.

An alternative preparation of compounds of Formula I-AC is shown inScheme 36.

where Q¹ and R¹ are as defined previously for compound of Formula I; andA¹¹=halogen such as Cl, Br, or I.

The compounds of Formula XXI may be prepared from aldehydes Q¹-CHO (seescheme 14 for their preparation) by addition of methyllithium or amethyl Grignard reagent, followed by oxidation of the resulting alcoholto the ketone of Formula XXI. Other compounds are commercially availableor can be prepared by methods well known to someone skilled in the art,see: Larock, R. C. Comprehensive Organic Transformations, 2^(nd) ed.;Wiley and Sons: New York, 1999, 1197ff. Reaction of compounds of FormulaXXI under typical halogenation conditions with typical halogenatingagents including, but not limited to, Br₂, NBS, pyridinium perbromide,or CuBr₂ (for A¹¹=Br), or NCS or SO₂Cl₂ (for A¹¹=Cl) gives the compoundsof Formula XXII. Their reaction with amines of Formula H₂N—R¹ gives theaminoketones of Formula XXIII that are converted to aminocyanopyrrolesof Formula XXIV by reaction with malononitrile under basic conditions.Finally, reaction of compounds of Formula XXIV under typical cyclizationconditions gives the compounds of Formula I-AC. Conditions for thiscyclization include, but are not limited to, heating with formamide;heating with formamide and ammonia; sequential treatment with a trialkylorthoformate, ammonia, and a base; sequential treatment with formamidineand ammonia.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

Compound of Formula I-AQ is equal to compound of Formula I whereinX₁=CH, X₂, X₃ and X₅=N, and X₄, X₆, and X₇=C:

Method AQ was used when preparing compounds of Formula I-AQ as shownbelow in Scheme 37:

Method AQ:

where Q¹ and R¹ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I and B(OR)₂=suitable boronic acid/ester.

In a typical preparation of compounds of Formula I-AQ, compound ofFormula II-Q was reacted with a suitable boronic acid/ester (Q¹-B(OR)₂)in a suitable solvent via typical Suzuki coupling procedures. Suitablesolvents for use in the above process included, but were not limited to,water, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was glyme/water. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 80° C. and about 100°C. The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of Formula I-AQ from II-Q. Forexample, compound of Formula II-Q could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula II-Q of Scheme 37 were prepared as shown belowin Scheme 38.

where R¹ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula II-Q, compound ofFormula III-Q was reacted with phosphorus oxychloride (POCl₃) andtriazole, and pyridine followed by ammonia (NH₃) in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −20° C. and about 50° C.Preferably, the reaction was carried out between 0° C. and about 25° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III-Q of Scheme 38 were prepared as shown belowin Scheme 39.

where R¹ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula III-Q, intermediateV-Q was converted to compound of Formula IV-Q. Intermediate of FormulaV-Q was treated with phosphorus oxychloride (POCl₃) in a suitablesolvent at a suitable reaction temperature. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like, chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃), and acetonitrile. Ifdesired, mixtures of these solvents were used. The preferred solvent wasacetonitrile. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 40° C. and about 95° C. The above process to produce compoundsof the present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Intermediate for Formula III-Q was prepared by reacting intermediate ofFormula IV-Q with a suitable halogenating agent. Suitable halogenatingagents included, but were not limited to, Br₂, I₂, Cl₂,N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. Thepreferred halogenating agent was N-iodosuccinimide. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, and the like; dimethylformamide(DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcohols such asmethanol, ethanol, isopropanol, trifluoroethanol, and the like; andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was DMF. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 75° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula V-Q of Scheme 39 were prepared as shown belowin Scheme 40:

where R¹ is as defined previously for compound of Formula I and A¹=OH,alkoxy, or a leaving group such as chloro or imidazole.

In a typical preparation, of a compound of Formula V-Q, a compound ofFormula VI-Q and compound of Formula V were reacted under suitableamide-coupling conditions. Suitable conditions include but are notlimited to treating compounds of Formula VI-Q and V (when A¹=OH) withcoupling reagents such as DCC or EDC in conjunction with DMAP, HOBt,HOAt and the like. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; halogenated solvents such as chloroform or methylenechloride. If desired, mixtures of these solvents were used, however thepreferred solvent was methylene chloride. The above process was carriedout at temperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about 22° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Alternatively, compounds of Formula VI-Q and V (where A¹=F, Cl, Br, I)were reacted with bases such as triethylamine or ethyldiisopropylamineand the like in conjunction with DMAP and the like. Suitable solventsfor use in this process included, but were not limited to, ethers suchas tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; pyridine; halogenated solventssuch as chloroform or methylene chloride. If desired, mixtures of thesesolvents were used, however the preferred solvent was DMF. The aboveprocess was carried out at temperatures between about −20° C. and about40° C. Preferably, the reaction was carried out between 0° C. and 25° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof compounds of Formula VI-Q and V (where A¹=F, Cl, Br, I) and base andsubstoichiometric amounts of DMAP were preferably used although higheror lower amounts were used if desired. Additionally, other suitablereaction conditions for the conversion of an amine (compound of FormulaVI-Q) to an amide (compound of Formula V-Q) can be found in Larock, R.C. Comprehensive Organic Transformations, 2^(nd) ed.; Wiley and Sons:New York, 1999, pp 1941-1949.

The compounds of Formula VI-Q of Scheme 40 were prepared as shown belowin Scheme 41:

In a typical preparation, of a compound of Formula VI-Q, a compound ofFormula VII-Q is reacted under suitable reaction conditions in asuitable solvent. Suitable conditions include treatment of compound ofFormula VII-Q with hydrazine in a suitable solvent. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, and the like; dimethylformamide(DMF); dimethyl sulfoxide (DMSO); acetonitrile; halogenated solventssuch as chloroform or methylene chloride; alcoholic solvents such asmethanol and ethanol. If desired, mixtures of these solvents may beused, however the preferred solvents were ethanol and methylenechloride. The above process was carried out at temperatures betweenabout 0° C. and about 80° C. Preferably, the reaction was carried out atabout 22° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantially,equimolar amounts of reactants were preferably used although higher orlower amounts were used if desired.

The compounds of Formula VII-Q of Scheme 41 were prepared as shown belowin Scheme 42:

In a typical preparation of a compound of Formula VII-Q, a compound ofFormula VIII-Q was reacted with Raney Nickel in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 100° C. Preferably, the reaction was carried out at about 80° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired. Additionally a compound of Formula VII-Q can beprepared by reacting a compound of Formula VIII-Q with a suitableoxidizing agent in a suitable solvent. A suitable oxidizing agentincludes, but is not limited to hydrogen peroxide (H₂O₂), 3-chloroperoxybenzoic acid (mCPBA) and the like. Suitable solvents for use inthe above process included, but were not limited to, ethers such as THF,glyme, and the like; DMF; DMSO; CH₃CN; and dimethylacetamide (DMA);chlorinated solvents such as CH₂Cl₂ or CHCl₃ If desired, mixtures ofthese solvents were used, however, the preferred solvent was DMA. Theabove process may be carried out at temperatures between about 0° C. and100° C. Preferably, the reaction was carried out at about rt to 70° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula VIII-Q of Scheme 42 were prepared as shownbelow in Scheme 43:

In a typical preparation of a compound of Formula VIII-Q, a compound ofFormula IX-Q was reacted with thiosemicarbazide and a suitable base in asuitable solvent. Suitable bases include, but were not limited totriethylamine, ethyldiisopropylamine and the like. Suitable solvents foruse in the above process included, but were not limited to, ethers suchas tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 100° C. Preferably, the reaction was carried out between about 40°C. and 80° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantially,equimolar amounts of reactants were preferably used although higher orlower amounts were used if desired. Compound of Formula IX-Q can beprepared according to literature procedures Knutsen, Lars J. S. et. al.,J. Chem. Soc. Perkin Trans 1: Organic and Bio-Organic Chemistry(1972-1999), 1984, 229-238.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

The following examples are intended to illustrate and not to limit thescope of the present invention.

General Experimental Information:

All melting points were determined with a MeI-Temp II apparatus and areuncorrected. Commercially available anhydrous solvents and HPLC-gradesolvents were used without further purification. ¹H NMR and ¹³C NMRspectra were recorded with Varian or Bruker instruments (400 MHz for ¹H,100.6 MHz for ¹³C) at ambient temperature with TMS or the residualsolvent peak as internal standards. The line positions or multiplets aregiven in ppm (δ) and the coupling constants (J) are given as absolutevalues in Hertz, while the multiplicities in ¹H NMR spectra areabbreviated as follows: s (singlet), d (doublet), t (triplet), q(quartet), quint (quintet), m (multiplet), m_(c) (centered multiplet),br (broadened), AA′BB′. The signal multiplicities in ¹³C NMR spectrawere determined using the DEPT135 pulse sequence and are abbreviated asfollows: +(CH or CH₃), −(CH₂), C_(quart) (C). LC/MS analysis wasperformed using a Gilson 215 autosampler and Gilson 819 autoinjectorattached to a Hewlett Packard HP 1100 and a MicromassZQ massspectrometer (also referred to as “OpenLynx”), or a Hewlett PackardHP1050 and a Micromass Platform II mass spectrometer. Both setups usedXTERRA MS C18 5μ 4.6×50 mm columns with detection at 254 nm andelectrospray ionization in positive mode. For mass-directed purification(MDP), a Waters/Micromass system was used.

The tables below list the mobile phase gradients (solvent A:acetonitrile; solvent B: 0.01% formic acid in HPLC water) and flow ratesfor the analytical HPLC programs.

Polar_(—)5 min

Flow Rate Flow Rate (mL/min) (mL/min) Time A % B % MicromassZQ PlatformII 0.00  5 95 1.3 1.3 3.00 90 10 1.3 1.3 3.50 90 10 1.3 1.3 4.00  5 951.3 1.3 5.00  5 95 1.3 1.3Nonpolar_(—)5 min

Flow Rate Flow Rate (mL/min) (mL/min) Time A % B % MicromassZQ PlatformII 0.00 25 75 1.3 1.3 3.00 99  1 1.3 1.3 3.50 99  1 1.3 1.3 4.00 25 751.3 1.3 5.00 25 75 1.3 1.3

Example 13-Cyclobutyl-1-(2-phenylquinolin-7-yl)-2H-imidazo[1,5-a]pyrazin-8-ylamine

Gaseous NH₃ is condensed into a cooled (dry ice/acetone) solution of7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline (160.0 mg,0.389 mmol) in 2M NH₃/iPrOH (4 mL) in a pressure tube until the volumeis doubled, then the tube is sealed and heated to 110° C. (bath temp.)for 15 h. The solvents are evaporated, and the crude material ischromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge,eluting with CH₂Cl₂ (1-7)→1% MeOH in CH₂Cl₂ (8-23)→2% MeOH in CH₂Cl₂(24-46)] to obtain the title compound as yellow solid; ¹H NMR (CDCl₃,400 MHz) δ 2.01-2.12 (m, 1H), 2.13-2.27 (m, 1H), 2.47-2.58 (m, 2H),2.62-2.73 (m, 2H), 3.85 (quint, J=8.0 Hz, 1H), 6.00 (brs, 2H), 7.04 (d,J=5.4 Hz, 1H), 7.15 (d, J=5.4 Hz, 1H), 7.46-7.51 (m, 1H), 7.52-7.58 (m,2H), 7.91 (dd, J=1.6, 8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.97 (d,J=8.0 Hz, 1H), 8.18-8.22 (m, 2H), 8.28 (d, J=8.4 Hz, 1H), 8.42 (d, J=0.8Hz, 1H). ¹³C NMR (CDCl₃, 100.6 MHz, DEPT135): δ=18.89 (−), 26.92 (2C,+), 31.50 (+), 106.62 (+), 114.32 (C_(quart)), 119.26 (+), 126.55(C_(quart)), 127.56 (3C, +), 128.06 (+), 128.15 (+), 128.83 (2C, +),129.44 (+), 129.67 (+), 134.56 (C_(quart)), 136.42 (C_(quart)), 136.53(+), 139.44 (C_(quart)), 144.40 (C_(quart)), 148.18 (C_(quart)), 151.62(C_(quart)), 157.94 (C_(quart)). MS (ES+): m/z 392.0 (100)[MH^(+]. HPLC: t) _(R)=1.7 min (MicromassZQ, nonpolar_(—)5 min).

7-(8-Chloro-3-cyclobutyl-2H-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline

A mixture of POCl₃ (5 mL, 8 g, 55 mmol) and cyclobutanecarboxylic acid[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)methyl]-amide [275 mg,0.583 mmol] is heated to 70° C. for 21.5 h. POCl₃ is evaporated, a coldsolution of NH₃ in iPrOH (2M, 11 mL, 22 mmol) is added, the suspensionis sonicated, the solid is filtered off and washed with iPrOH. The solidis suspended in CHCl₃ and filtered, and the filtrate is concentrated toobtain the title compound as yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ2.04-2.15 (m, 1H), 2.15-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.64-2.76 (m,2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.44-7.50 (m,1H), 7.51-7.57 (m, 3H), 7.89-7.93 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (dd,J=0.8, 8.8 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H). MS (ES+): m/z 410.9/412.9(100/39) [MH⁺]. HPLC: t_(R)=3.7 min (MicromassZQ, nonpolar_(—)5 min).

Cyclobutanecarboxylic acid[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-amide

To a solution of NEt(iPr)₂ (150 μL, 111 mg, 0.861 mmol), DMAP (5 mg,0.04 mmol), andC-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (202 mg,0.583 mmol) in dry CH₂Cl₂ (5 mL), cooled by ice/water, is addedcyclobutanecarbonyl chloride (75 μL, 78 mg, 0.66 mmol), then the coolingbath is removed, and the reaction mixture is stirred at rt for 3 h.Water is added, the layers are separated, and the aqueous layer isextracted with CH₂Cl₂ (3×15 mL). The combined CH₂Cl₂ layers are washedwith water, saturated NaHCO₃ solution, and brine, dried over MgSO₄,filtered and concentrated to give crude material as yellow foam, whichis used for the next step without purification. ¹H NMR (CDCl₃, 400 MHz)δ 1.81-1.90 (m, 1H), 1.90-2.02 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m,2H), 3.12 (quint, J=8.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0Hz, 1H), 7.43-7.48 (m, 1H), 7.48-7.54 (m, 2H), 7.73 (dd, J=2.0, 8.4 Hz,1H), 7.82 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.90 (d, J=0.8 Hz,1H), 8.07-8.12 (m, 2H), 8.19 (d, J=8.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H),8.58 (d, J=2.4 Hz, 1H). MS (ES+): m/z 429.0/431.0 (38/13) [MH⁺],469.8/471.8 (6/2) [MH⁺+MeCN]. HPLC: t_(R)=3.6 min (MicromassZQ,polar_(—)5 min).

C-(3-Chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine

A solution of2-[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-isoindole-1,3-dione(1.536 g, 3.22 mmol) and anhydrous hydrazine (335 μL, 342 mg, 10.7 mmol)in EtOH (2 mL)/CH₂Cl₂ (12 mL) is stirred at it overnight. The whiteprecipitate formed (phthalic hydrazide) is filtered off and washed withCH₂Cl₂. The combined filtrate and washings are concentrated in vacuo,the residue is suspended in CDCl₃ and filtered (0.45 μM pore size), andthe filtrate is concentrated in vacuo to obtain the title compound asyellow foam, which is used for the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 2.4 (brs, 2H), 5.79 (s, 1H),7.43-7.55 (m, 3H), 7.61 (dd, J=1.8, 8.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H),7.86 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 8.10-8.15 (m, 2H), 8.19(d, J=8.8 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H). MS(ES+): m/z 347.0/349.0 (30/10) [MH⁺], 330.0/332.0 (18/6) [MH⁺—NH₃].HPLC: t_(R)=2.1 min (MicromassZQ, polar_(—)5 min).

2-[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-isoindole-1,3-dione

To a suspension of(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methanol (1.215 g, 3.49mmol), phthalimide (566 mg, 3.85 mmol), and PS-PPh₃ (loading 2.12mmol/g; 3.29 g, 6.97 mmol) in dry THF (40 mL), cooled by ice/water, isadded DIAD (830 μL, 852 mg, 4.22 mmol). The cooling bath is removed andthe flask is vortexed at it for ld. More phthalimide (50 mg, 0.34 mmol),PS-PPh₃ (300 mg, 0.636 mmol), and DIAD (80 μL, 82 mg, 0.41 mmol) areadded, and vortexing is continued for 2d. The resin is filtered off on aglass frit (porosity M) and washed with CH₂Cl₂. The combined filtratesand washings are concentrated in vacuo and chromatographed on silica gel[Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH₂Cl₂ (1-22)→2%EtOAc in CH₂Cl₂ (23-38)→5% (39-61)], mixed fractions are combined andchromatographed again [50 g/150 mL cartridge, eluting with CH₂Cl₂(1-22)→2% EtOAc in CH₂Cl₂ (23-33)→3% (34-55)→5% (56-68)] to obtain thetitle compound as white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.14 (s, 1H),7.43-7.55 (m, 3H), 7.72-7.79 (m, 3H), 7.82-7.90 (m, 4H), 8.09 (s, 1H),8.09-8.14 (m, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.51(d, J=2.4 Hz, 1H). MS (ES+): m/z 476.9/478.9 (100/38) [MH⁺]. HPLC:t_(R)=3.5 min (MicromassZQ, nonpolar_(—)5 min).

(3-Chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methanol

To a solution of 2,2,6,6-tetramethylpiperidine (0.820 mL, 0.686 g, 4.86mmol) in dry THF (15 mL), cooled by CO₂(s)/acetone, is added nBuLi (2.5Min hexanes; 1.95 mL, 4.88 mmol). The cooling bath is replaced with anice/water bath for 15 min, and then the solution is re-cooled to −78° C.After 5 min, a solution of 2-chloropyrazine (0.370 mL, 0.475 g, 4.14mmol) in THF (0.5 mL) is added. 25 min later, a solution of2-phenylquinoline-7-carbaldehyde (890 mg, 3.82 mmol) in dry THF (7 mL)is added slowly over 5 min from a syringe which is then rinsed with THF(1 mL), and the mixture is stirred at −78° C. for 2 h and then warmed upto 0° C. for 0.5 h. The reaction is quenched by adding citric acid(0.25M aqueous solution). The mixture is extracted with EtOAc (4×30 mL),and the combined EtOAc extracts are washed with water, sodium bicarbsolution, and brine and dried over MgSO₄. The crude material ischromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge,eluting with CH₂Cl₂ (4×50 mL, then 1-16)→2% EtOAc in CH₂Cl₂ (17-30)→5%(31-59)→7% (60-85)→10% (86-110)] to obtain the title compound as anoff-white foam. ¹H NMR (CDCl₃, 400 MHz) δ 4.80 (d, J=7.6 Hz, 1H), 6.25(d, J=7.6 Hz, 1H), 7.43-7.56 (m, 3H), 7.58 (dd, J=1.8, 8.2 Hz, 1H), 7.83(d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.06 (brs, 1H), 8.10-8.15 (m,2H), 8.20 (d, J=8.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.62 (d, J=2.4 Hz,1H). MS (ES+): m/z 348.0/350.0 (100/37) [MH⁺]. HPLC: t_(R)=3.3 min(MicromassZQ, polar_(—)5 min).

2-Phenylquinoline-7-carbaldehyde

A mixture of 7-methyl-2-phenylquinoline (2.49 g, 11.4 mmol) and seleniumdioxide (1.92 g, 17.3 mmol, 1.5 eq.) is heated to 160° C. (bath temp.)for 22 h. The cooled melt is suspended in CH₂Cl₂ with the aid ofsonication and filtered through Celite and then through a plug of silicagel. This effectively removes the red color and the major lower spots.The material thus obtained is crystallized from hexanes/CHCl₃, yieldinga pale beige solid, mp. 108° C. The mother liquor is concentrated andchromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge,eluting with hexanes:CH₂Cl₂ 1:1 (1-25)→1:3 (26-53)→CH₂Cl₂ (54-73)→3%EtOAc in CH₂Cl₂ (74-85)] to obtain as pale yellow solid, mp. 109° C. ¹HNMR (CDCl₃, 400 MHz) δ 7.48-7.60 (m, 3H), 7.94 (d, J=8.8 Hz, 1H),8.01-8.05 (m, 2H), 8.18-8.23 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 8.64 (s,1H), 10.26 (s, 1H). MS (ES+): m/z 234.2 (100) [MH⁺]. HPLC: t_(R)=3.0 min(MicromassZQ, nonpolar_(—)5 min); ¹³C NMR (CDCl₃, 100.6 MHz, DEPT135) δ121.22 (+), 122.80 (+), 127.51 (2C, +), 128.65 (+), 128.94 (2C, +),129.83 (+), 130.69 (C_(quart)), 135.84 (+), 136.68 (+), 137.21(C_(quart)), 138.79 (C_(quart)), 147.91 (C_(quart)), 158.48 (C_(quart)),192.14 (+); IR (film): v=3059 cm⁻¹, 3034, 2824, 2717, 1954, 1812, 1684,1601, 1554, 1510, 1491, 1448, 1420, 1392, 1320, 1280, 1168, 1145, 1120,1075, 1052, 1025, 971, 926, 897, 850, 812, 787, 757, 692, 673, 627.

7-Methyl-2-phenylquinoline

To a solution of 7-methylquinoline (1.63 g, 11.4 mmol) in dry THF (10mL), cooled by ice/water, is added phenyllithium (1.9M incyclohexane/ether 70/30, 6.0 mL, 11.4 mmol) dropwise over 5 min. After15 min, the cooling bath is removed, and the solution is stirred at itfor 5 h. The reaction is quenched by adding MeOH, and stirring iscontinued overnight. Water is added, the mixture is extracted with EtOAc(3×35 mL), and the combined extracts are dried over MgSO₄. The dryingagent is filtered off, and air is bubbled into the solution for 7d. Thesolvent is evaporated; the residue is dissolved in warm (≈50° C.)EtOAc/hexanes and filtered warm. The filtrate is concentrated and driedin vacuo to obtain the crude title compound that is used directly forthe next step. Further purification is possible by chromatography onsilica gel (Jones Flashmaster, eluting with hexanes:EtOAc 3:1→2:1→1:1).¹H NMR (CDCl₃, 400 MHz) δ 2.58 (s, 3H), 7.31 (d, J=3.7 Hz, 1H),7.36-7.49 (m, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.82(d, J=8.2 Hz, 1H), 7.96 (s, 1H), 8.16 (t, J=8.0 Hz, 2H). MS (ES+): m/z220.3 (100) [MH⁺]. HPLC: t_(R)=2.7 min (Platform II, nonpolar_(—)5 min).

Additionally, 2-phenylquinoline-7-carbaldehyde could be prepared asfollows: To a solution of (2-phenylquinolin-7-yl)methanol (75 mg, 0.319mmol) in chloroform (1 mL) was added MnO₂ (277 mg, 3.19 mmol). Themixture was stirred at it for 20 h and filtered through a Celite pad.The filtrate was concentrated under reduced pressure and the residue waspurified by silica gel chromatography. (1% MeOH in dichloromethane) toafford the title compound. ¹H-NMR (CDCl₃, 400 MHz) δ 7.50-7.59 (m, 3 H),7.95 (d, J=8.8 Hz, 1 H), 8.04 (dd, J=2.4, 8.8 Hz, 2 H), 8.19-8.22 (m, 2H), 8.31 (d, J=8.8 Hz, 1 H), 8.69 (s, 1 H), 10.26 (s, 1 H). MS (ES+):m/z 234 [MH⁺]. HPLC: t_(R)=3.59 min (OpenLynx, polar_(—)5 min).

(2-Phenylquinolin-7-yl)methanol

Under N₂, to a solution of 2-phenylquinoline-7-carboxylic acidhydrochloride (144 mg, 0.5 mmol) in THF (5 mL) was added LiAlH₄ (95 mg,2.5 mmol) in two portions. The mixture was stirred at it for 15 h,quenched with water (1 mL), and filtered through a Celite pad, which waswashed with EtOAc (30 mL). The combined filtrates were dried over MgSO₄,filtered, concentrated, and purified by silica gel chromatography (5%MeOH in dichloromethane) to afford the desired product. ¹H-NMR (CDCl₃,400 MHz) δ 4.93 (s, 2 H), 7.46-7.57 (m, 4 H), 7.84 (d, J=8.4 Hz, 1 H),7.88 (d, J=8.8 Hz, 1 H), 8.14-8.18 (m, 3 H), 8.23 (d, J=8.4 Hz, 1 H). MS(ES+): m/z 236 [MH⁺]. HPLC: t_(R)=2.72 min (OpenLynx, polar_(—)5 min).

2-Phenylquinoline-7-carboxylic acid hydrochloride

Iron powder (21.05 g, 377 mmol), water (8 mL), and concentratedhydrochloric acid (0.63 mL, ˜7.5 mmol) were added consecutively to asolution of methyl 4-formyl-3-nitrobenzoate (8.04 g, 38.4 mmol) in EtOH(100 mL). The mixture was stirred at 95° C. for 1.5 h. Acetophenone (4.4mL, 37.7 mmol) and solid KOH (6.344 g, 113 mmol) were then added withcaution. This mixture was stirred at 95° C. for another 5 h. Theinorganic solids were filtered off when still warm and the filtrate wasacidified to pH=˜1.0 with 4 N HCl(aq). The solvents were removed andwater (10 mL) was added. The product was extracted into THF (100 mL×3),dried over MgSO₄, filtered, concentrated to afford the desired productas HCl salt; ¹H-NMR (CD₃OD, 400 MHz) δ 7.73-7.80 (m, 3 H), 8.17-8.20 (m,2 H), 8.40-8.48 (m, 3 H), 9.02 (d, J=0.8 Hz, 1H), 9.17 (d, J=8.8 Hz, 1H). MS (ES+): m/z 250 [MH⁺]. HPLC: t_(R)=3.18 min (OpenLynx, polar_(—)5min).

Example 2trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid amide

An isopropanol solution (20 mL) oftrans-4-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methyl ester (2.0 g, 4.0 mmol) in a sealed tube was cooled to −78°C. Ammonia was bubbled into the solution for 5 min; the tube was cappedand heated to 110° C. for 1d. The reaction mixture was concentrated invacuo and partitioned b/w CHCl₃ and water. The aqueous layer wasextracted with CHCl₃ (5×) and the combined organic layers were driedover Na₂SO₄, filtered, charged with silica gel, and concentrated toyellow solids. The crude material was purified by silica gel columnchromatography [Jones Flashmaster, 20 g/70 mL cartridge, eluting with5%˜7 N NH₃ in MeOH, 5% MeOH/CHCl₃]. The purified material wasrecrystallized from MeOH/CHCl₃/diethyl ether to afford the desiredproduct as a light yellow solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.56-1.73(m, 4H), 1.85-1.91 (m, 2H), 2.01-2.06 (m, 2H), 2.17-2.25 (m, 1H),3.12-3.20 (m, 1H), 6.35 (s, 2H), 6.70 (s, 1H), 7.09 (d, 1H, J=4.8 Hz),7.26 (s, 1H), 7.51-7.59 (m, 3H), 7.73 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H,J=2.0 Hz, 8.4 Hz), 8.09 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 8.23(s, 1H), 8.30 (d, 2H, J=7.6 Hz), 8.51 (d, 1H, J=8.4 Hz). MS (ES+): m/z463.0 [MH⁺]; HPLC: t_(R)=2.1 min (Micromass Platform II, polar_(—)5min).

trans-4-[8-Chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methyl ester

A CH₂Cl₂ solution (2 mL) oftrans-4-{[(3-chloropyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-cyclohexanecarboxylicacid methyl ester (2.3 g, 4.5 mmol) in a round bottom flask equippedwith a condenser was charged with POCl₃ (15 mL) and stirred at 80° C.for 72 h. The reaction mixture was concentrated in vacuo to a foam,cooled to 0° C., and charged with cold 2M NH₃ in isopropanol to basicpH. The mixture was concentrated in vacuo to solids and partitionedbetween EtOAc and water. The organic layer was washed with water (1×),brine (1×), dried over Na₂SO₄, filtered, and concentrated to a brownoil. The resulting residue was purified by silica gel chromatography(CH₂Cl₂ to 1%˜7N NH₃ in MeOH/CH₂Cl₂) to provide the desired product as ayellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m,2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s,3H), 7.39 (d, 1H, J=5.2 Hz), 7.45-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.61(d, 1H, J=5.2 Hz), 7.85-7.93 (m, 3H), 8.19 (d, 2H, J=7.6 Hz), 8.27 (d,1H, J=8.4 Hz), 8.50 (s, 1H); MS (ES+): m/z 496.9 [MH⁺]; HPLC: t_(R)=3.6min (Micromass Platform II, nonpolar_(—)5 min).

trans-4-{[(3-Chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-carbamoyl}-cyclohexanecarboxylicacid methyl ester

A THF solution (15 mL) of CDI (1.2 g, 7.3 mmol) andtrans-4-carbomethoxycyclohexane-1-carboxylic acid (1.2 g, 6.6 mmol) wasstirred at 60° C. for 16 h. The reaction mixture was charged withC-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (compoundof Formula IV where Q¹=2-phenylquinolin-7-yl) (2.3 g, 6.6 mmol) andstirred at 60° C. for 20 h. The reaction mixture was concentrated invacuo, taken up in EtOAc, and washed with water (2×) and brine (1×). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The resulting residue was purified by silica gel chromatography(20% EtOAc/Hexanes to 100% EtOAc) the desired product as an orange foam;¹H NMR (CDCl₃, 400 MHz) δ 1.48-1.55 (m, 4H), 1.95-2.06 (m, 4H),2.17-2.24 (m, 1H), 2.26-2.33 (m, 1H), 3.66 (s, 3H), 6.77 (d, 1H, J=7.6Hz), 7.36-7.41 (m, 1H), 7.45-7.55 (m, 3H), 7.72-7.77 (m, 1H), 7.81-7.89(m, 2H), 8.11 (d, 2H, J=7.2 Hz), 8.20-8.25 (m, 1H), 8.39 (d, 1H, J=2.4Hz), 8.60 (d, 1H, J=2.8 Hz); MS (ES+): m/z 515.0 [MH⁺]; HPLC: t_(R)=3.1min (Micromass Platform II, nonpolar_(—)5 min).

Example 3trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methyl ester

An isopropanol solution (20 mL) oftrans-4-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methyl ester (2.0 g, 4.0 mmol) in a sealed tube was cooled to −78°C. Ammonia was bubbled into the solution for 5 min; the tube was cappedand heated to 110° C. for 1d. The reaction mixture was concentrated invacuo and partitioned between CHCl₃ and water. The aqueous layer wasextracted with CHCl₃ (5×) and the combined organic layers were driedover Na₂SO₄, filtered, charged with silica gel, and concentrated toyellow solids. The crude material was purified by silica gel columnchromatography [Jones Flashmaster, 20 g/70 mL cartridge, eluting with2%˜7 N NH₃ in MeOH/CH₂Cl₂] to afford the desired product as a yellowsolid; ¹H NMR (CDCl₃, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m, 2H),2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s, 3H),5.25 (s, 2H), 7.13 (d, 1H, J=4.8 Hz), 7.27-7.28 (m, 1H), 7.46-7.50 (m,1H), 7.52-7.57 (m, 2H), 7.89-7.96 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d,1H, J=8.8 Hz), 8.40-8.42 (m, 1H); MS (ES+): m/z 478.0 [MH⁺]; HPLC:t_(R)=2.5 min (Micromass Platform II, polar_(—)5 min).

Example 4

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid

A THF solution (2 mL) oftrans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methyl ester was charged with 10M NaOH (0.31 mL, 3.1 mmol); aminimal amount of methanol was added to homogenize the reaction mixture.The reaction stirred at rt for 2 h. The reaction mixture wasconcentrated to solids and acidified to pH 5 with 2M HCl. The aqueouslayer was extracted with CHCl₃ (5×) and combined organic layers weredried over Na₂SO₄, filtered, and concentrated to the desired compound asa orange solid; ¹H NMR (CDCl₃, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02(m, 2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72(s, 3H), 5.25 (s, 2H), 6.91 (d, 1H, J=6.0 Hz), 7.29-7.33 (m, 1H),7.51-7.59 (m, 3H), 7.81 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.00-8.05 (m, 2H),8.21-8.23 (m, 2H), 8.32 (d, 1H, J=9.2 Hz), 8.41-8.42 (m, 1H); MS (ES+):m/z 464.0 [MH⁺]; HPLC: t_(R)=2.3 min (Micromass Platform II, polar_(—)5min).

Example 5trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methylamide

A DMF solution (3 mL) oftrans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid (260 mg, 0.56 mmol) and methylamine hydrochloride (379 mg, 5.6mmol) in a sealed tube was charged with DIEA (0.98 mL, 5.6 mmol), 0.6MHOAt in DMF (0.93 mL, 0.56 mmol), and then EDC (161 mg, 0.84 mmol). Thereaction mixture stirred at it for 16 h. The reaction mixture wasconcentrated to solids, taken up in CH₂Cl₂, charged with silica, andconcentrated to brown solids. The crude material was purified by silicagel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge,eluting with 2%˜7N NH₃ in MeOH/CH₂Cl₂]. The purified material wasrecrystallized from MeOH/CH₂Cl₂/diethyl ether to the desired product asa light yellow solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.56-1.73 (m, 4H),1.85-1.91 (m, 2H), 2.01-2.06 (m, 2H), 2.17-2.25 (m, 1H), 2.52 (d, 3H,J=4.4 Hz), 3.12-3.20 (m, 1H), 6.17 (s, 2H), 7.09 (d, 1H, J=4.8 Hz),7.51-7.59 (m, 4H), 7.73 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H, J=2.0 Hz, 8.4Hz), 8.09 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 8.23 (s, 1H), 8.30(d, 2H, J=7.6 Hz), 8.51 (d, 1H, J=8.4 Hz); MS (ES+): m/z 477.0[MH⁺];HPLC: t_(R)=2.1 min (Micromass Platform II, polar_(—)5 min).

Example 6trans-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol

A THF solution (8 mL) oftrans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylicacid methyl ester was cooled to −78° C. and charged with 1M LiAlH₄ inTHF (1.5 mL, 1.5 mmol) dropwise; the reaction vessel was removed fromthe −78° C. cooling bath and stirred at rt for 4 h. The reaction mixturewas charged with EtOAc, Na₂SO₄.10H₂O, and silica gel and concentrated invacuo to yellow solids. The crude material was purified by silica gelcolumn chromatography [Jones Flashmaster, 10 g/70 mL cartridge, elutingwith 1%˜7N NH₃ in MeOH/CH₂Cl₂] to afford the desired product as a yellowsolid; ¹H NMR (CDCl₃, 400 MHz) δ 1.17-1.29 (m, 2H), 1.63-1.73 (m, 2H),1.87-2.07 (m, 4H), 2.12-2.23 (m, 2H), 2.92-3.02 (m, 1H), 3.56 (d, 2H,J=6.0 Hz), 5.25 (s, 2H), 7.13 (d, 1H, J=4.8 Hz), 7.27-7.28 (m, 1H),7.46-7.50 (m, 1H), 7.52-7.57 (m, 2H), 7.89-7.96 (m, 3H), 8.18-8.21 (m,2H), 8.27 (d, 1H, J=8.8 Hz), 8.40-8.42 (m, 1H); MS (ES+): m/z 450.0[MH⁺]; HPLC: t_(R)=2.4 min (Micromass Platform H, polar_(—)5 min).

Example 7trans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione

trans-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol(290 mg, 0.47 mmol), phthalimide (82 mg, 0.56 mmol), and resin-boundtriphenylphosphine (PS-Ph₃P [Argonaut, 2.16 mmol/g]) (324 mg) weredissolved in 2.5 mL of THF, evacuated, placed under nitrogen atmosphereand charged with DIAD (0.11 mL, 0.56 mmol). After stirring for 16 h, theresin was filtered, washed with CH₂Cl₂ (5×) and concentrated to anorange-colored oil. The crude material was purified by silica gel columnchromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 1%MeOH/CH₂Cl₂ to 2%˜7N NH₃ in MeOH/CH₂Cl₂] to afford the desired productas a yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 1.17-1.29 (m, 2H),1.60-1.61 (m, 1H), 1.87-2.07 (m, 4H), 2.12-2.23 (m, 2H), 2.92-3.02 (m,1H), 3.64 (d, 2H, J=6.8 Hz), 5.25 (s, 2H), 7.11 (d, 1H, J=5.6 Hz),7.24-7.26 (m, 1H), 7.45-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.72-7.75 (m,2H), 7.86-7.95 (m, 5H), 8.17-8.20 (m, 2H), 8.25 (d, 1H, J=8.8 Hz),8.38-8.39 (m, 1H); MS (ES+): m/z 579.0 [MH⁺]; HPLC: t_(R)=2.9 min(Micromass Platform II, nonpolar_(—)5 min).

Example 8trans-3-(4-Aminomethylcyclohexyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

An ethanolic solution oftrans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione(265 mg, 0.46 mmol) was charged with an excess of hydrazine (0.14 mL,4.6 mmol) and allowed to stir at rt for 16 h. The solution was filteredthrough a fritted glass funnel and the solids were washed with EtOH(4×). The filtrate was concentrated and the crude material was purifiedby silica gel column chromatography [Jones Flashmaster, 5 g/25 mLcartridge, eluting with 2%˜7 N NH₃ in MeOH/CH₂Cl₂ to 4%˜7N NH₃ inMeOH/CH₂Cl₂]. The purified material was recrystallized fromCH₂Cl₂/hexanes to afford the desired product as a yellow solid; ¹H NMR(CDCl₃, 400 MHz) δ 1.16-1.26 (m, 2H), 1.58-1.65 (m, 1H), 1.87-1.99 (m,2H), 2.02-2.09 (m, 2H), 2.13-2.22 (m, 2H), 2.72 (d, 2H, J=6.4 Hz),2.92-3.01 (m, 1H), 7.10 (d, 1H, J=5.2 Hz), 7.25-7.28 (m, 1H), 7.42-7.55(m, 3H), 7.89-7.94 (m, 3H), 8.18-8.20 (m, 2H), 8.24 (d, 1H, J=8.8 Hz),8.39-8.41 (m, 1H); MS (ES+): m/z 449.0 [MH⁺]; HPLC: t_(R)=2.0 min(Micromass Platform II, nonpolar_(—)5 min).

Example 93-Methyl-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

7-(8-Chloro-3-methyl-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline wasdissolved in 10.0 mL of 2.0M NH₃ in IPA and 5.0 mL of CH₂Cl₂. Thereaction was heated to 110° C. for 64 h. The salts were filtered off andwashed with CH₂Cl₂. Purified with silica gel column chromatography[Jones Flashmaster, 10 g cartridge, eluting with 1% MeOH:EtOAc] to yielda dark yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 2.71 (s, 3H), 5.61 (brs,2H), 7.13 (d, 1H, J=5.1 Hz), 7.2 (d, 1H, J=5.1 Hz), 7.48-7.56 (m, 3H),7.89-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, 1H, J=8.6 Hz), 8.39 (s,1H); MS (ES+): 352.06 (M+1), 353.07 (M+2), 354.09 (M+3).

7-(8-Chloro-3-methyl-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline

N-[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-acetamide(273.0 mg, 0.702 mmol) was dissolved in 20 mL of POCl₃. The reaction washeated to 80° C. for 24 h. The excess POCl₃ was removed in vacuo. Theresidue was worked up by basifying with cold 2.0 M NH₃ in IPA followedby the addition of CH₂Cl₂ and water. The aqueous layer was washed withCH₂Cl₂ (2×). The organic layers where combined, dried over sodiumsulfate, filtered and concentrated in vacuo to yield a light brown oil;¹H NMR (400 MHz, CDCl₃) δ 2.77 (s, 3H), 7.41-7.59 (m, 4H), 7.70-7.72 (m,1H), 7.88-7.93 (m, 3H), 8.19-8.28 (brm, 3H), 8.55 (brs, 1H); MS (ES+):370.96 (M+1), 372.97 (M+3), 373.98 (M+4).

N-[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-acetamide

C-(3-Chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (250mg, 0.72 mmol) was dissolved in 4.0 mL of CH₂Cl₂ and DIPEA (139.8 mg,1.08 mmol) and DMAP (8.8 mg, 0.07 mmol) were added. The reaction wascooled to 0° C. and acetyl chloride (68 mg, 0.87 mmol) was added to thehomogenous reaction mixture. After 3 h the reaction was complete. Waterwas added and the organic layer was washed with NaHCO₃ sat. aq. sol(1×), H₂O and Brine. The organic layers where combined, dried oversodium sulfate, filtered and concentrated in vacuo. The crude productwas purified with silica gel column chromatography [Jones Flashmaster,10 g cartridge, eluting with 2% MeOH: CH₂Cl₂] to yield a dark oil; ¹HNMR (400 MHz, CDCl₃) δ 2.08 (s, 3H), 6.80 (d, 1H, J=7.9 Hz), 7.26-7.23(m, 4H), 7.70-7.92 (m, 4H), 8.09-8.11 (m, 2H), 8.17 (d, 1H, J=8.60 Hz),8.37 (d, 1H, J=2.40 Hz), 8.57 (d, 1H, J=2.49 Hz); MS (ES+): 430.84(M+1), 432.83 (M+3), 433.92 (M+4).

Example 103-Isopropyl-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

3-Isopropyl-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylaminewas prepared utilizing the same procedures as those used for Example 9except isobutyryl chloride was used in place of acetyl chloride; ¹H NMR(400 MHz, CDCl₃) δ 1.24 (d, 6H, J=7.04 Hz), 2.47-2.53 (m, 1H), 6.80 (d,1H, J=7.83 Hz), 7.26-7.23 (m, 4H), 7.70-7.92 (m, 411), 8.09-8.11 (m,2H), 8.17 (d, 1H, J=8.60 Hz), 8.37 (d, 1H, J=2.50 Hz), 8.57 (d, 1H,J=2.49 Hz); MS (ES+): 486.91 (M+1), 488.86 (M+3), 489.94 (M+4).

Example 111-(6-Chloro-2-phenyl-quinolin-7-yl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine

1-(6-Chloro-2-phenyl-quinolin-7-yl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamineand its intermediates herein were prepared according to the proceduresdescribed for Example 1, except6-chloro-2-phenyl-quinoline-7-carbaldehyde was used in place of2-phenyl-quinoline-7-carbaldehyde: ¹H NMR (CDCl₃, 400 MHz) δ 2.02-2.24(m, 2H), 2.48-2.70 (m, 4H), 3.87 (quintet, 1H, J=8.6 Hz), 4.80 (brs,2H), 7.09 (d, 1H, J=5.2 Hz), 7.19 (d, 1H, J=4.8 Hz), 7.46-7.56 (m, 3H),7.98 (d, 1H, J=8.8 Hz), 8.02 (s, 1H), 8.16-8.22 (m, 3H), 8.35 (s, 1H);MS (ES+): 426.0/427.9 (M/M+2).

6-Chloro-7-(8-chloro-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline

¹H NMR (CDCl₃, 400 MHz) δ 2.01-2.22 (m, 2H), 2.48-2.70 (m, 4H), 3.91(quintet, 1H, J=8.6 Hz), 7.36 (d, 1H, J=4.8 Hz), 7.45-7.58 (m, 4H),7.93-7.97 (m, 2H), 8.15-8.22 (m, 3H), 8.33 (s, 1H); MS (ES+):444.9/446.9 (M/M+2).

Cyclobutanecarboxylic acid[(6-chloro-2-phenyl-quinolin-7-yl)-(3-chloro-pyrazin-2-yl)-methyl]-amide

¹H NMR (CDCl₃, 400 MHz) δ 1.85-1.98 (m, 2H), 2.15-2.38 (m, 4H), 3.13(quintet, 1H, J=8.4 Hz), 6.63 (d, 1H, J=8.0 Hz), 7.15 (d, 1H, J=8.0 Hz),7.46-7.53 (m, 3H), 7.82 (s, 1H), 7.90 (d, 1H, J=8.8 Hz), 7.93 (s, 1H),8.06-8.08 (m, 2H), 8.15 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.4 Hz), 8.58(d, 1H, J=2.4 Hz); MS (ES+): 462.8/464.8 (M/M+2.

C-(6-Chloro-2-phenyl-quinolin-7-yl)-C-(3-chloro-pyrazin-2-yl)-methylamine

¹H NMR (CDCl₃, 400 MHz) δ 6.11 (s, 1H), 7.44-7.53 (m, 3H), 7.80 (s, 1H),7.89 (d, 1H, J=8.8 Hz), 7.91 (s, 1H), 8.06-8.09 (m, 2H), 8.15 (d, 1H,J=8.8 Hz), 8.37 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz); MS (ES+):380.9/383.0 (M/M+2).

2-[(6-Chloro-2-phenyl-quinolin-7-yl)-(3-chloro-pyrazin-2-yl)-methyl]-isoindole-1,3-dione

¹H NMR (CDCl₃, 400 MHz) δ 7.36 (s, 1H), 7.43-7.55 (m, 3H), 7.76-7.78 (m,2H), 7.82-7.94 (m, 5H), 8.05-8.07 (m, 2H), 8.18 (d, 1H, J=5.6 Hz), 8.41(d, 1H, J=2.4 Hz), 8.55 (d, 1H, J=2.0 Hz); MS (ES): 510.8/512.7 (M/M+2).

(6-Chloro-2-phenyl-quinolin-7-yl)-(3-chloro-pyrazin-2-yl)-methanol

¹H NMR (CDCl₃, 400 MHz) δ 4.67 (d, 1H, J=7.2 Hz), 6.64 (d, 1H, J=7.2Hz), 7.46-7.53 (m, 3H), 7.70 (s, 1H), 7.90 (d, 1H, J=8.8 Hz), 7.95 (s,1H), 8.05-8.07 (m, 2H), 8.16 (d, 1H, J=8.4 Hz), 8.47 (d, 1H, J=2.4 Hz),8.65 (d, 1H, J=2.4 Hz); MS (ES): 381.9/383.9 (M/M+2).

6-Chloro-2-phenyl-quinoline-7-carbaldehyde

The CCl₄ (45 ml) solution of 6-chloro-7-methyl-2-phenylquinoline (753.3mg, 2.969 mmol), AIBN (48.8 mg, 0.1 eq.) and NBS (898.4 mg, 1.7 eq.) washeated at 80° C. under N₂ for 8 h. After that time, the reaction mixturewas concentrated in vacuo and the residue was dissolved in EtOAc (60ml), washed successively with H₂O (30 mL), saturated NaS₂O₃ (30 mL), H₂O(30 mL), and brine (30 mL). The organic extract was then dried (MgSO₄),filtered and concentrated in vacuo. The residue was dissolved in DMSO(105 mL), and then NaHCO₃ (2495 mg, 10 eq.) was added. The reactionmixture was stirred at 90° C. for 3 h. Water (140 mL) was added and themixture was extracted with EtOAc (3×200 mL). The combined organicextracts were washed with H₂O (4×60 mL) and brine (60 mL), and dried(MgSO₄), filtered, and concentrated in vacuo. The residue wasrecrystallized from CHCl₃/hexane (20:80, 10 mL) to give6-chloro-2-phenylquinoline-7-carbaldehyde as pale-yellow solid; ¹H NMR(CDCl₃, 400 MHz) δ 7.51-7.58 (m, 3H), 7.93 (s, 1H), 8.03 (d, 1H, J=8.8Hz), 8.18-8.20 (m, 3H), 8.75 (s, 1H), 10.63 (s, 1H); MS (ES+):268.1/270.0 (M/M+2).

6-Chloro-7-methyl-2-phenyl-quinoline

Into a solution of 6-chloro-7-methylquinoline (1000 mg, 5.644 mmol) inTHF (5 mL), which was cooled in ice/water bath under N₂, was added PhLi(1.9 M in THF, 2.971 mL) dropwise over 5 min. After stirring at 0° C.for 15 min, the ice/water bath was removed and the reaction mixture wasstirred at rt. After 4 h, MeOH (5 mL) was added to quench the reactionand the reaction mixture was stirred at rt overnight. After that time,the mixture was poured into water (20 mL) and extracted with EtOAc (3×30mL). The organic extracts were dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was dissolved in acetonitrile (30 mL)and DDQ (1282 mg) was added and the solution was stirred under N₂ at rtfor 24 h. After that time, the reaction mixture was poured into aqueousNaOH (3 N, 50 mL) and extracted with EtOAc (2×75 mL). The extracts werewashed with aqueous NaOH (3N, 2×50 mL), water (2×50 mL) and brine (50mL), dried over MgSO₄, filtered, and concentrated in vacuo to afford thetitle compounds; ¹H NMR (CDCl₃, 400 MHz) δ 2.60 (s, 3H), 7.47-7.55 (m,3H), 7.83-7.86 (m, 2H), 8.04 (s, 1H), 8.10-8.16 (m, 3H); MS (ES):254.1/256.1 (M/M+2).

Example 123-tert-Butyl-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

Gaseous NH₃ was condensed into a cooled (−78° C.) solution of7-(3-tert-butyl-8-chloroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline(92.5 mg, 0.224 mmol) in NH₃/i-PrOH (2M, 5 mL) in a pressure tube untilthe volume had doubled. The tube was sealed and heated to 110° C. for 21h. After excess NH₃ and i-PrOH were removed in vacuo, the residue wassuspended between CH₂Cl₂ and water, the layers were separated, and theaqueous layer was extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were washed with brine (3×25 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The crude material was purified by chromatographyon silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH(7N NH₃):CH₂Cl₂ 1%→2%], affording the title compound, as a fine yellowsolid. ¹H NMR (CDCl₃, 400 MHz) δ 1.25 (s, 914), 5.18 (s, —NH₂), 7.08 (d,J=4.8 Hz, 1H), 7.45-7.51 (m, 1H), 7.51-7.57 (m, 3H), 7.90-7.97 (m, 3H),8.17-8.22 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.42-8.44 (m, 1H); MS (ES+):m/z 394.1 (25) [MH⁺]; HPLC: t_(R)=2.5 min (OpenLynx, polar_(—)5 min).

7-(3-tert-Butyl-8-chloroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline

To a solution ofN-[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-2,2-dimethylpropionamide(264 mg, 0.612 mmol) in THF (3 mL), cooled to 0° C., KOtBu (800 μL, 1 M,0.796 mmol) was added, the cooling bath was removed, and the reactionmixture stirred at ambient temperature for 30 min, under N₂. THF wasremoved in vacuo, POCl₃ (25 mL, 42 g, 0.273 mol) was added to theresidue, and the reaction mixture was vortexed at 70° C., under N₂, for5 d. POCl₃ was evaporated (min. 2 h on high-vacuum), a cold solution ofNH₃/i-PrOH (2M, 10 mL) was added, the suspension was filtered, and thesolid was washed several times with i-PrOH. The filtrate wasconcentrated, extracted with CH₂Cl₂ (3×30 mL), washed with brine (50mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crudematerial was dissolved in CH₂Cl₂, adsorbed onto Hydromatrix, andpurified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mLcartridge, eluting with EtOAc:CH₂Cl₂ 2%→5%], yielding the titlecompound, as a yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (s, 9H),7.33 (d, J=4.8 Hz, 1H), 7.44-7.50 (m, 1H), 7.50-7.58 (m, 2H), 7.87-7.94(m, 4H), 8.17-8.22 (m, 2H), 8.24-8.30 (m, 1H), 8.51 (s, 1H); MS (ES+):m/z 412.9/414.9 (100/38) [MH⁺]; HPLC: t_(R)=4.3 min (OpenLynx,polar_(—)5 min).

N-[(3-Chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-2,2-diethylpropion-amide

To a solution ofC-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (231.4mg, 0.6672 mmol), DMAP (4 mg, 0.033 mmol), and (iPr)₂EtN (174 μL, 129mg, 1 mmol) in dry CH₂Cl₂ (5 mL), cooled to 0° C., pivaloyl chloride (90μL, 89 mg, 0.734 mmol) was added under N₂ atmosphere, the cooling bathwas removed, and the reaction mixture was allowed to stir at ambienttemperature for 16 h. The reaction was quenched with H₂O and extractedwith CH₂Cl₂ (3×20 mL). The combined CH₂Cl₂ layers were washed with (1×30mL each) 0.25M citric acid (pH 2-3), H₂O, NaHCO₃ sat. aq. sol., andbrine, dried over anhydrous MgSO₄, and filtered. Sample was purified byfiltration through a plug of silica gel, eluting with EtOAc:CH₂Cl₂10:1→5:1 (300 mL). Filtrate was concentrated in vacuo, yielding thetitle compound, as a yellow solid, containing approximately 10% ofbis-acetylated material; ¹H NMR (CDCl₃, 400 MHz) δ 1.23 (s, 9H), 6.75(d, J=7.6 Hz, 1H), 7.43-7.48 (m, 1H), 7.49-7.55 (m, 2H), 7.60 (d, br,J=7.6 Hz, —NH), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 7.90 (s, 1H),8.07-8.14 (m, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.59(d, J=2.0 Hz, 1H); MS (ES+): m/z 430.9/432.9 (100/37) [MH⁺]; HPLC:t_(R)=3.5 min (OpenLynx, polar_(—)5 min).

Example 133-Cyclobutyl-1-(2-thiophen-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

To a cooled (ice/water) solution of3-cyclobutyl-1-quinolin-7-ylimidazo[1,5-a]pyrazin-8-ylamine (52.7 mg,0.167 mmol) in THF (5 mL) was added 2-thienyllithium (1 M in THF; 0.6mL, 0.6 mmol), then the cooling bath was removed, and the solution wasstirred overnight at ambient temperature. After 1d and 2 d, more2-thienyllithium (0.2 mL, 0.2 mmol) was added, and stirring wascontinued. The reaction was quenched by adding water and sat. NH₄Clsolution, the mixture was extracted with CH₂Cl₂ (3×20 mL), and thecombined organic extracts were washed with brine and dried over MgSO₄.Air was bubbled into the solution for 8 h. The crude material wasadsorbed onto Hydromatrix and chromatographed on silica gel [JonesFlashmaster, 5 g/25 mL cartridge, eluting with CH₂Cl₂ (1-6)→1% MeOH inCH₂Cl₂ (7-21)→2% MeOH in CH₂Cl₂ (22-43)], yielding a yellow film.Further purification by preparative TLC (20×20 cm silica gel plates, 500μM thickness, eluting with 3% MeOH in CH₂Cl₂ four times) yielded thetitle compound as a yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 2.01-2.12(m, 1H), 2.13-2.27 (m, 1H), 2.47-2.58 (m, 2H), 2.62-2.73 (m, 2H), 3.85(quint, J=8.0 Hz, 1H), 5.40 (brs, 2H), 7.08 (brd, J=4.8 Hz, 1H), 7.14(d, J=4.8 Hz, 1H), 7.17 (dd, J=3.6, 5.2 Hz, 1H), 7.48 (dd, J=1.2, 5.2Hz, 1H), 7.76 (dd, J=1.2, 3.6 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.88-7.91(m, 2H), 8.28 (dd, J=8.8, 0.8 Hz, 1H), 8.34 (d, J=0.8 Hz, 1H); MS (ES+):m/z 398.0 (60) [MH⁺].

3-Cyclobutyl-1-quinolin-7-yl-imidazo[1,5-a]pyrazin-8-ylamine

Gaseous NH₃ was condensed into a cooled (dry ice/acetone) solution of7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline (203.2 mg,0.607 mmol) in 2M NH₃/iPrOH (6 mL) in a pressure tube until the volumewas doubled, then the tube was sealed and heated to 110° C. (bath temp.)for 19 h. The ammonia was evaporated, the crude material was adsorbedonto Hydromatrix and chromatographed on silica gel [Jones Flashmaster,10 g/70 mL cartridge, eluting with CH₂Cl₂ 1:1 (1-6)→2% MeOH in CH₂Cl₂(7-27)→4% MeOH in CH₂Cl₂ (28-37)→5% MeOH in CH₂Cl₂ (38-53)→7% MeOH inCH₂Cl₂ (54-67)], yielding the title compound as a yellow solid, >98%pure by HPLC, mp. 94-96° C.; ¹H NMR (CDCl₃, 400 MHz) δ 2.00-2.10 (m,1H), 2.12-2.25 (m, 1H), 2.47-2.57 (m, 2H), 2.61-2.73 (m, 2H), 3.85(quint, J=8.4 Hz, 1H), 5.23 (brs, 2H), 7.10 (d, J=4.4 Hz, 1H), 7.16 (d,J=4.4 Hz, 1H), 7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),8.00 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.36 (s, 1H), 8.95-9.00(m, 1H); MS (ES+): m/z 316.2 (30) [MH⁺].

7-(8-Chloro-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-quinoline

A mixture of POCl₃ (8 mL, 13 g, 87 mmol) and cyclobutanecarboxylic acid[(3-chloropyrazin-2-yl)-quinolin-7-ylmethyl]-amide (566 mg, 1.60 mmol)was heated to 55° C. for 21.5 h and to 70° C. for 6 h. POCl₃ wasevaporated, a cold solution of NH₃ in iPrOH (2 M, 10 mL) was added, thesuspension was filtered, and the solid was washed with iPrOH. The crudematerial contained in the combined filtrate and washings was adsorbedonto Hydromatrix and chromatographed on silica gel [Jones Flashmaster,20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-13)→1:3(14-38)], yielding the title compound as a yellow foam; ¹H NMR (CDCl₃,400 MHz) δ 2.05-2.14 (m, 1H), 2.16-2.28 (m, 1H), 2.50-2.60 (m, 2H),2.63-2.75 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H),7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.90 (d, J=8.4 Hz,1H), 8.13 (dd, J=1.6, 8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.46 (s, 1H),8.98 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 335.1/337.1 (100/44) [MH⁺].

Cyclobutanecarboxylic acid[(3-chloro-pyrazin-2-yl)-quinolin-7-yl-methyl]-amide

To a solution of NEt(iPr)₂ (520 μL, 386 mg, 2.99 mmol), DMAP (12 mg,0.098 mmol), and C-(3-chloropyrazin-2-yl)-C-quinolin-7-ylmethylamine(compound of Formula IV where Q¹=quinolin-7-yl) (608 mg, 1.97 mmol) indry CH₂Cl₂ (10 mL), cooled by ice/water, was added cyclobutanecarbonylchloride (250 μL, 260 mg, 2.19 mmol), then the cooling bath was removed,and the reaction mixture was stirred at ambient temperature for 2.5 h.Water was added, the layers were separated, and the aqueous layer wasextracted with CH₂Cl₂ (3×20 mL). The combined CH₂Cl₂ layers were washedwith dilute HCl (pH 2), water, saturated NaHCO₃ solution, and brine anddried over MgSO₄. The crude material is chromatographed on silica gel[Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1(1-21)→1:3 (22-44)→EtOAc (45-56)], yielding the title compound as anorange foam; ¹H NMR (CDCl₃, 400 MHz) δ 1.81-1.91 (m, 1H), 1.91-2.03 (m,1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.6 Hz, 1H),6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0, 8.0 Hz,1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.83 (s, 1H), 8.13(d, J=8.4 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.87(dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 353.1/355.0 (100/39) [MH⁺].

C-(3-Chloro-pyrazin-2-yl)-C-quinolin-7-yl-methylamine

A solution of2-[(3-chloropyrazin-2-yl)-quinolin-7-ylmethyl]-isoindole-1,3-dione (789mg, 1.97 mmol) and anhydrous hydrazine (63 μL, 64 mg, 2.0 mmol) in EtOH(4 mL)/CH₂Cl₂ (2 mL) was stirred at ambient temperature for 1d. Morehydrazine (93 μL, 95 mg, 3.0 mmol) was added, and stirring was continuedfor 2 d. The solid formed (phthalic hydrazide) was filtered off andwashed with EtOH, and the combined filtrate and washings were dried toyield a red, sticky solid. This solid was suspended in CH₂Cl₂ andfiltered, and the filtrate was concentrated to give the title compoundas an orange gum; ¹H NMR (CDCl₃, 400 MHz) δ 2.4 (brs, 2H), 5.79 (s, 1H),7.39 (dd, J=4.2, 8.2 Hz, 1H), 7.64 (dd, J=1.8, 8.6 Hz, 1H), 7.81 (d,J=8.4 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 8.13 (dd, J=0.8, 8.0 Hz, 1H),8.31 (d, J=2.4 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.4 Hz,1H); MS (ES+): m/z 271.0/273.0 (30/10) [MH⁺], 254.1/256.1 (30/10)[MH⁺—NH₃].

2-[(3-Chloro-pyrazin-2-yl)-quinolin-7-yl-methyl]-isoindole-1,3-dione

To a suspension of (3-chloropyrazin-2-yl)-quinolin-7-ylmethanol (600 mg,2.21 mmol), phthalimide (356 mg, 2.42 mmol), and PS—PPh₃ (loading 2.12mmol/g; 1.56 g, 3.31 mmol) in dry THF (20 mL), cooled by ice/water, wasadded DIAD (480 μL, 493 mg, 2.44 mmol), then the cooling bath wasremoved and the flask was vortexed at ambient temperature for 21.5 h.More PS—PPh₃ (520 mg, 1.10 mmol) and DIAD (160 μL, 164 mg, 0.81 mmol)were added, and vortexing was continued for 6.5 h. The resin wasfiltered and washed with THF and CH₂Cl₂. The crude material waschromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge,eluting with hexanes:EtOAc 3:1 (1-14)→2:1 (15-29)→1:1 (30-65)→1:2(66-80)], yielding the title compound as pale yellow solid; ¹H NMR(CDCl₃, 400 MHz) δ 7.12 (s, 1H), 7.41 (dd, J=4.4, 8.0 Hz, 1H), 7.54 (dd,J=2.0, 8.4 Hz, 1H), 7.72-7.78 (m, 2H), 7.81-7.89 (m, 3H), 8.01 (d, J=0.8Hz, 1H), 8.16 (dd, J=0.8, 8.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.50 (d,J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 401.0/402.9(100/38) [MH⁺].

(3-chloropyrazin-2-yl)-quinolin-7-ylmethanol

To a solution of 2,2,6,6-tetramethylpiperidine (0.64 mL, 0.54 g, 3.8mmol) in dry THF (10 mL), cooled by CO₂(s)/acetone, was added nBuLi (2.5M in hexanes; 1.6 mL, 4.0 mmol). The cooling bath was replaced with anice/water bath for 15 min, and then the solution was re-cooled to −78°C. After 10 min, 2-chloropyrazine (0.29 mL, 0.37 g, 3.2 mmol) was added.A solution of quinoline-7-carbaldehyde (500 mg, 3.18 mmol) in dry THF (5mL), cooled by CO₂(s)/acetone, was transferred into thelithiochloropyrazine solution by cannula 30 min later, and the mixturewas stirred at −78° C. for 2.5 h and at 0° C. for 0.5 h. The reactionwas quenched by adding aq. HCl (2 mL of a 2 M solution) followed by aq.NH₄Cl solution. The mixture was extracted with EtOAc (4×30 mL), combinedEtOAc extracts were washed with water and brine and dried over MgSO₄.The crude material was chromatographed on silica gel [Jones Flashmaster,20 g/70 mL cartridge, eluting with hexanes:EtOAc 2:1 (1-21)→1:1(22-32)→1:4 (33-62)→EtOAc (63-66)], yielding the title compound as anorange foam; ¹H NMR (CDCl₃, 400 MHz) δ 4.87 (d, J=7.6 Hz, 1H), 6.26 (d,J=7.6 Hz, 1H), 7.41 (dd, J=4.4, 8.4 Hz, 1H), 7.60 (dd, J=1.6, 8.4 Hz,1H), 7.82 (d, J=8.4 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 8.14 (dd, J=0.8,8.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.91 (dd,J=1.6, 4.4 Hz, 1H). MS (ES+): m/z 272.1/274.1 (100/38) [MH⁺].

Example 14cis-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid amide

Through a suspension ofcis-methyl-3-(8-chloro-1-(2-phenylquinolin-7-ylimidazo[1,5-a]pyrazin-3-yl)cyclobutanecarboxylate(153 mg, 0.32 mmol) in isopropanol (15 mL) in a Parr vessel at −70° C.was bubbled ammonia for 2 minutes. The vessel was sealed and thetemperature was raised to 110° C. and the reaction was left to stir for20 h. The reaction mixture was then cooled in a dry ice bath andtransferred to a round-bottomed flask and concentrated in vacuo. Thecrude product was purified via MDP, to afford the title compound as ayellow solid; MS (ES+): m/z 435.29 (80) [MH⁺]; ¹H NMR (400 MHz, DMSO-d₆)δ 2.54-2.59 (m, 4H) 3.04-3.12 (m, 1H) 3.84-3.92 (m, 1H) 6.23 (bs, 1H)6.82 (bs, 1H) 7.10 (d, J=4.8 Hz, 1H) 7.52-7.59 (m, 4H) 7.94 (dd, J=6.8,1.6 Hz, 1H) 8.10 (d, J=8.4 Hz, 1H) 8.18 (d, J=9.2 Hz, 1H) 8.24-8.25 (m,1H) 8.30-8.32 (m, 21-1) 8.51 (d, J=8 Hz, 1H).

cis-3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid methyl ester andtrans-3-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid methyl ester

To a solution of3-(8-chloro-1-(2-phenylquinolin-7-ylimidazo[1,5-a]pyrazin-3-yl)cyclobutanecarbaldehyde(3.274 g, crude, 7.43 mmol) in MeOH (125 mL) was added NIS (10 g, 44.55mmol) and potassium carbonate (6.2 g, 44.55 mmol). The reaction flaskwas wrapped in aluminum foil and the reaction stirred at rt in the darkfor 20 h. The mixture was then quenched with water (100 mL), dilutedwith DCM, and subsequently washed with sodium thiosulfate, brine, andconcentrated in vacuo. The product was purified via silica gelchromatography (1:1 EtOAc:Hex) to afford the individual cis and transproducts as yellow solids.

trans-3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid methyl ester

MS (ES+): m/z 469.2 (100) [MH+]; ¹H NMR (400 MHz, CDCl₃) δ 2.76-2.84 (m,2H) 2.94-3.01 (m, 2H) 3.27-3.40 (m, 1H) 3.72 (s, 3H) 3.79-3.87 (m, 1H)7.38 (d, J=5.2 Hz, 1H) 7.45-7.49 (m, 1H) 7.52-7.56 (m, 2H) 7.63 (d,J=4.8 Hz, 1H) 7.89-7.93 (m, 3H) 8.18-8.20 (m, 2H) 8.27 (d, J=8.0 Hz, 1H)8.51 (s, 1H).

cis-3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid methyl ester

MS (ES+): m/z 469.2 (100) [MH+]; ¹H NMR (400 MHz, CDCl₃) δ 2.81-2.86 (m,2H) 2.92-2.99 (m, 2H) 3.33-3.41 (m, 1H) 3.77 (s, 3H) 4.04-4.10 (m, 1H)7.38 (d, J=5.2 Hz, 1H) 7.45-7.49 (m, 1H) 7.52-7.56 (m, 2H) 7.63 (d,J=4.8 Hz, 1H) 7.89-7.93 (m, 3H) 8.18-8.20 (m, 2H) 8.27 (d, J=8.0 Hz, 1H)8.51 (s, 1H).

3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarbaldehyde

To a solution of oxalyl chloride (1.87 mL, 21.4 mmol) in anhydrous DCM(17.3 mL) was added a solution of DMSO (3.1 mL, 42.9 mmol) in DCM (8.58mL) at −72° C. The reaction stirred for 30 minutes prior to the additionof[3-(8-chloro-1-(2-phenylquinolin-7-ylimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol(1.9 g, 4.29 mmol) in DCM (20 mL) at the same temperature. After 30minutes, the reaction was quenched with triethylamine (15 mL, 107.2mmol) and was slowly warmed to rt. The mixture was diluted with DCM (50mL), washed with water, NaHCO₃ (sat), brine, dried over Na₂SO₄ andconcentrated in vacuo, to afford a mixture of isomers; MS (ES+): ink441.1 (80) [MH+].

Example 15trans-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid amide

This compound was prepared utilizing the same procedures as those usedfor Example 14 excepttrans-methyl-3-(8-chloro-1-(2-phenylquinolin-7-ylimidazo[1,5-a]pyrazin-3-yl)cyclobutanecarboxylatewas used in place ofcis-methyl-3-(8-chloro-1-(2-phenylquinolin-7-ylimidazo[1,5-a]pyrazin-3-yl)cyclobutanecarboxylate;MS (ES+): m/z 435.29 (40) [MH+]; ¹H NMR (400 MHz, DMSO-d₆) δ 2.53-2.70(m, 4H) 3.16-3.20 (m, 1H) 3.90-3.97 (m, 1H) 6.24 (bs, 2H) 6.84 (bs, 1H)7.09 (d, J=5.1 Hz, 1H) 7.31 (bs, 1H) 7.45 (d, J=4.0 Hz, 1H) 7.50-7.60(m, 3H) 7.96 (dd, J=6.6, 1.8 Hz, 1H) 8.11 (d, J=8.3 Hz, 1H) 8.19 (d,J=8.6 Hz, 1H) 8.28 (s, 1H) 8.30-8.33 (m, 2H) 8.52 (d, J=9.1 Hz, 1H).

Example 16cis-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid

This compound was prepared utilizing the same procedures as those usedfor the synthesis ofcis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylicacid amide except the reaction was monitored at short intervals tominimize the amide formation. The reaction generated a mixture of esterand amide (2:1), which was treated with NaOH (0.15 mL) in THF (0.95 mL)and MeOH (1 mL). The reaction was left to stir at rt for 3 h. Themixture was concentrated in vacuo, diluted with DCM and washed withwater. The product was purified by MDP, to afford the title compound asa yellow solid; MS (ES+): m/z 436.27 (40) [MH+]; ¹H NMR (400 MHz,DMSO-d₆) δ 2.62-2.67 (m, 5H) 3.16 (s, 1H) 3.90-3.91 (m, 1H) 6.21 (s, 1H)7.10 (d, J=5.2 Hz, 1H) 7.50-7.59 (m, 4H) 7.93 (dd, J=6.8, 1.6 Hz, 1H)8.10 (d, J=8.4 Hz, 1H) 8.18 (d, J=8.8 Hz, 1H) 8.25 (s, 1H) 8.30-8.33 (m,2H) 8.51 (d, J=8.4 Hz, 1H).

Example 171-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine

4-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-piperidine-1-carboxylicacid benzyl ester (1.6 g, 2.8 mmol) was suspended in a solution of 2MNH₃ in isopropanol (200 mL) in a 300 mL Parr vessel and cooled to −78°C. Ammonia gas was bubbled into the solution for 6 min and then thevessel was sealed and heated to 115° C. for 24 h. The solution wascooled to rt and transferred to a round bottom flask. Hydromatrix wasadded, the mixture was concentrated in vacuo, and the resulting residuewas purified by silica gel chromatography (Jones Flashmaster, 25 g/150mL cartridge, eluting with 5% 7N NH₃ in methanol/CH₂Cl₂) to afford amixture of4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-piperidine-1-carboxylicacid benzyl ester and1-(2-Phenylquinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamineas a yellow solid. Dissolved mixture in 37% HCl (45.0 mL) and heated to60° C. for 2 min. Cooled to rt and diluted solution with water andwashed with ether (2×) and CH₂Cl₂ (1×). Added 5N NaOH to aqueoussolution until basic and filtered off1-(2-Phenylquinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamineas a yellow solid, which was purified by silica gel chromatography(Jones Flashmaster, 2 g/12 mL cartridge, eluting with 5% 7N NH₃ inmethanol/CH₂Cl₂) to afford the title compound as a yellow solid; ¹H NMR(DMSO-d₆, 400 MHz): δ 1.72-1.88 (m, 4H), 2.65-2.71 (m, 2H), 3.05 (d, 2H,J=12.0 Hz), 3.22-3.33 (m, 2H), 6.21 (bs, 2H), 7.09 (d, 1H, J=4.8 Hz),7.50-7.59 (m, 3H), 7.70 (d, 1H, J=5.2 Hz), 7.92 (dd, 1H, J=8.4, 1.6 Hz),8.09 (d, 1H, J=8.0 Hz), 8.17 (d, 1H, J=8.8 Hz), 8.24 (bs, 1H), 8.31 (dd,2H, J=8.8, 1.6 Hz), 8.51 (d, 1H, J=8.4 Hz); MS (ES+): m/z 421 (10)[MH⁺]; HPLC: t_(R)=1.7 min (OpenLynx, polar_(—)5 min).

4-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-piperidine-1-carboxylicacid benzyl ester

4-{[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]carbamoyl}-piperidine-1-carboxylicacid benzyl ester (2.1 g, 3.6 mmol) was dissolved in CH₃CN (126.0 mL)and DMF (0.4 mL) in a round bottom flask equipped with a condenser. Thereaction was charged with POCl₃ (1.7 mL, 17.9 mmol) and stirred at 55°C. for 3 h. The reaction mixture was concentrated in vacuo, redissolvedin DCM, cooled to 0° C., and charged with 2M NH₃ in isopropanol to basicpH. Hydromatrix was added, the mixture was concentrated in vacuo, andthe resulting residue was purified by silica gel chromatography (JonesFlashmaster, 20 g/70 mL cartridge, eluting with 100% CH₂Cl₂ to 2%CH₃CN/CH₂Cl₂) to afford4-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-piperidine-1-carboxylicacid benzyl ester as a yellow solid; MS (ES+): m/z 574 (100) [MH⁺];HPLC: t_(R)=4.2 min (OpenLynx, polar_(—)5 min).

4-{[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylicacid benzyl ester

A CH₂Cl₂ solution (111.0 mL) ofC-(3-chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (1.9 g,5.5 mmol) and PS-DIPEA (2.8 g, 11.1 mmol) in a round bottom flask underN₂ atmosphere was charged with 4-chlorocarbonyl-piperidine-1-carboxylicacid benzyl ester (1.4 g, 5.0 mmol) and stirred at it for 1.5 h. Thereaction mixture was filtered and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (Jones Flashmaster, 20g/70 mL cartridge, eluting with 100% CH₂Cl₂ to 10% CH₃CN/CH₂Cl₂) toafford4-{[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylicacid benzyl ester as a pale yellow solid: MS (ES+): m/z 592/594 (100/50)[MH⁺]; HPLC: t_(R)=3.7 min (OpenLynx, polar_(—)5 min).

Example 181-{4-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone

1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine-trisHCl salt (59.0 mg, 0.1 mmol) was dissolved in triethylamine (1.0 mL) andDMF (0.5 mL). Acetic anhydride (12.0 μL, 0.1 mmol) was added and thereaction was stirred for 1 h. The reaction was concentrated in vacuo andpurified by silica gel chromatography (Jones Flashmaster, 2 g/12 mLcartridge, eluting with 2% 7N NH₃ in methanol/CH₂Cl₂). The sample wasfurther purified using MDPS to yield1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanoneas a pale yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 1.95 (ddd, 1H, J=22.4,11.2, 4.0 Hz), 2.03-2.23 (m, 6H), 2.90 (ddd, 1H, J=13.6, 13.6, 2.8 Hz),3.19-3.32 (m, 2H), 4.01 (bd, 1H, J=13.6 Hz), 4.64 (bd, 1H, J=13.2 Hz),5.44 (bs, 2H), 7.11 (d, 1H, J=4.8 Hz), 7.24 (d, 1H, J=5.6 Hz), 7.46(ddd, 1H, J=6.0, 2.4, 0.8 Hz), 7.50-7.54 (m, 2H), 7.86-7.94 (m, 3H),8.16 (ddd, 2H, J=7.2, 3.6, 1.6 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.38 (s,1H); MS (ES+): m/z 463 (10) [MH⁺]; HPLC: t_(R)=2.1 min (OpenLynx,polar_(—)5 min).

Example 194-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-N-ethylpiperidine-1-carboxamide

4-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-N-ethylpiperidine-1-carboxamidewas synthesized using the same procedure as1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanoneexcept ethylisocyanate was used instead of acetic anhydride; yellowpowder; MS (ES+): m/z 492.10 (70) [MH⁺], 493.11 (45) [MH⁺²], 211.41(100) [MH-280]; HPLC: t_(R)=2.08 min (polar-5 min/openlynx).

Example 203-{1-[(Dimethylamino)acetyl]piperidin-4-yl}-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine

To a solution of3-piperidin-4-yl-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-aminein CH₂Cl₂ (2 mL), chloroacetyl chloride (73 mg, 0.64 mmol, 51 μL) andPS-DIEA (384 mg, 1.43 mmol) were added. The reaction was allowed toshake at it for 1 h. The reaction mixture was absorbed onto silica gel,and purified by silica gel column chromatography [Jones Flashmaster, 25g/150 mL cartridge, eluting with 100% CH₂Cl₂ to 5% 7N[NH3/CH₃OH]/CH₂Cl₂] to obtain the desired chloroketone intermediate,which was transferred to a glass pressure reaction vessel and dissolvedin 2M dimethylamine solution in THF (9 mL). The reaction was heated at80° C. for 18 h. The reaction was absorbed onto silica gel and purified[Jones Flashmaster, 10 g/70 mL cartridge, eluting with 100% CH₂Cl₂ to 5%7N [NH3/CH₃OH]/CH₂Cl₂] to obtain the desired product. The product wasfurther purified by trituration with 10% DMSO in 1:1 THF/CH₃OH to affordthe desired product as a light yellow powder; ¹H NMR (CDCl₃, 400 MHz) δ8.42 (dd, J=1.0, 1.0 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.20 (m, 2H), 7.96(d, J=8.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H),7.57 (m, 2H), 7.29 (d, J=4.8 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 5.30 (brd, J=4.0 Hz, 1H), 4.66 (m, 1H), 4.30 (m, 1H), 3.76 (m, 2H), 3.33-3.22(m, 4H), 2.97 (m, 1H), 2.38 (s, 6H), 2.30-1.90 (m, 5H), 1.86 (m, 1H); MS(ES+): m/z 56.12 (20) [MH⁺], 507.09 (10) [MH⁺²], 421.13 (50) [M-85],253.85 (100) [MH-252]; HPLC t_(R)=1.73 min (polar-5 min/openlynx).

Example 214-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylicacid benzyl ester

Benzyl4-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylicacid benzyl ester (1.50 g, 2.55 mmol) was dissolved in anhydrous2-propanol (70.0 mL, 916 mmol) in a Parr bombs. The solution was cooledto −78° C. and ammonia was bubbled into the solution for 4 min. The bombwas sealed, stirred and heated to 110° C. for 3 days. The solvent wasevaporated in vacuo. The residue was purified by a 25 g Jones silica gel(eluted with 5% MeOH/EtOAc), which afforded the desired product; ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.41 (1 H, d, J=8.4), 8.30 (1 H, d, J=8.64Hz), 8.21 (2 H, dd, J=1.58 Hz, J=1.18), 8.00 (2 H, m), 7.84 (1 H, dd,J=1.74, J=1.74), 7.54 (3 H, m), 7.37 (5 H, s), 7.24 (1 H, d, J=5.54),7.00 (1 H, d, J=5.53), 5.13 (2H, s), 4.23 (2H, m), 2.96 (2 H, d,J=7.08), 2.82 (2 H, m), 2.04 (1 H, m), 1.80 (2H, m), 1.31 (2H, m); MS(ES+): m/z 569.17/570.16 (100/65) [MH⁺]; HPLC: t_(R)=2.56 min (OpenLynx,polar_(—)5 min).

4-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylicacid benzyl ester

A solution of4-({[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-methyl)-piperidine-1-carboxylicacid benzyl ester in anhydrous acetonitrile (165 mL) was charged withPOCl₃ (2.03 mL, 21.84 mmol) and DMF (2.15 mL) and heated to 55° C. underN₂ condition. After 2 h, LC/MS and TLC analysis showed the reaction tobe completed. The reaction mixture was concentrated in vacuo, dilutedwith CH₂Cl₂, and quenched with 2N (7N NH₃) in 2-propanol to pH 9.2-Propanol was removed in vacuo. The crude product was purified bysilica gel flash chromatography (loaded with 40% EtOAc/Hexanes, and run50% EtOAc/Hexanes→80% EtOAc/Hexanes), which afforded the desiredproduct; ¹H NMR (400 MHz, DMSO-d) δ ppm 8.53 (1 H, d, J=8.52), 8.45 (1H, d, J=5.00), 8.31 (3 H, m), 8.21 (1 H, d, J=8.66), 8.08 (1 H, d,J=8.47), 7.56 (3 H, m), 7.49 (1 H, d, J=5.00), 7.34 (5 H, m), 5.07 (2 H,s), 4.02 (2 H, d, J=12.8), 3.32 (2 H, s), 3.11 (2 H, d, J=6.92), 2.82 (1H, m), 2.13 (1 H, m), 1.73 (2 H, d, J=12.26), 1.21 (2 H, m); MS (ES+):m/z 589.97 (5) [MH⁺]; HPLC: t_(R)=3.72 min (OpenLynx, polar_(—)5 min).

4-({[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-methyl)-piperidine-1-carboxylicacid benzyl ester

(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)-methanamine (120.00 mg,0.35 mmol), EDC (100.64 mg, 0.53 mmol) and HOBt (47.29 mg, 0.35 mmol)were suspended in CH₂Cl₂ (2 mL) and charge with DIEA (122.00 μL, 0.70mmol) followed by the addition of 1-N-Cbz-4-piperidineacetic acid(127.56 mg, 0.46 mmol). The reaction mixture was stirred at rt for 16 h.The reaction mixture was diluted with CH₂Cl₂ (10 mL) and washed withsaturated NaHCO₃ (2×20 mL) and brine (2×20 mL). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo. The crude product waspurified by a 10 g Jones silica gel (wetted with 50% EtOAc/Hexane, driedloaded onto silica, and run with 60% EtOAc/Hexanes→70% EtOAc/Hexanes)affording the desired product; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (1H, d, J=2.47), 8.39 (1 H, d, J=2.50), 8.23 (1 H, d, J=4.77), 8.11 (2 H,d, J=7.06), 7.85 (3 H, dd, J=8.60, J=8.38), 7.74 (1 H, s), 7.50 (3 H,m), 7.32 (6H, m), 6.78 (1 H, d, J=7.76), 5.10 (2 H, s), 4.11 (2 H, m),2.75 (2 H, m), 2.21 (2 H, d, J=7.00), 2.01 (1 H, m), 1.67 (2 H, m), 1.15(2 H, d, J=8.921); MS (ES+): m/z 605.96/606.98/608.93 (100/40/15) [MH⁺];HPLC: t_(R)=3.33 min. (OpenLynx, nonpolar_(—)5 min.).

Example 221-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine

4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylicacid benzyl ester (1.94 g, 3.41 mmol) was mixed with 37% HCl (90.00 mL,3.96 mol), heated to 60° C. and continued to stir for 5 mins. It wasthen cooled to rt, washed with ether (2×90 mL) and then with CH₂Cl₂(2×90 mL). The aqueous layer was gradually basified with 5N NaOH andextracted with CH₂Cl₂ (3×50 mL). The combined organic layer was driedwith Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by a 25 g Jones silica gel (eluted with 10% (7N NH₃) inMeOH/EtOAc), affording the desired product; ¹H NMR (400 MHz, METHANOL-d)δ 8.38 (1 H, d, J=8.68), 8.24 (1 H, d, J=0.74 Hz), 8.08 (2 H, dd, J=1.55Hz, J=1.19), 8.00 (2 H, m), 7.80 (1 H, dd, J=1.68, J=1.70), 7.51 (1 H,d, J=5.14), 7.44 (3 H, m), 6.99 (1 H, d, J=5.10), 2.99 (2 H, d,J=12.60), 2.94 (2 H, d, J=7.20), 2.55 (2 H, t), 2.01 (1 H, m), 1.66 (2H,d, J=12.72), 1.29 (2 H, m); MS (ES+): m/z 435.12/436.10 (15/5) [MH⁺];HPLC: t_(R)=1.71 min (OpenLynx, polar_(—)5 min).

Example 233-(1-Ethyl-piperidin-4-ylmethyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

Acetaldehyde (6.76 mg, 0.15 mmol) in dichloroethane (5 mL, 2 equiv) wasadded to1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine(100.00 mg, 0.23 mmol) and sodium triacetoxyborohydride (65.0 mg, 306.8mmol). The reaction mixture was stirred at rt overnight. The crudeproduct was purified by a 5 g Jones silica gel (dry loaded with silica,wetted with 100% CH₂Cl₂, eluted with 100% CH₂Cl₂→3% (7N NH₃) inMeOH/CH₂Cl₂→6% (7N NH₃) in MeOH/CH₂Cl₂) and afforded the desiredproduct. ¹H NMR (400 MHz, METHANOL-d) δ 8.38 (1 H, d, J=8.66), 8.25 (1H, s), 8.08 (2 H, dd, J=1.64 Hz, J=1.08), 8.00 (2 H, m), 7.79 (1 H, dd,J=2.06, J=1.70), 7.51 (1 H, d, J=5.15), 7.44 (3 H, m), 7.00 (1 H, d,J=5.12), 3.06 (2 H, d, J=10.88), 2.97 (2 H, d, J=7.08), 2.54 (2 H, d,J=5.80), 2.18 (2 H, m), 1.98 (1H, m), 1.75 (2 H, d, J=13.12), 1.43 (2 H,m), 1.07 (3 H, t); MS (ES+): m/z 435.12/436.10 (15/5) [MH⁺]; HPLC:t_(R)=1.71 min (OpenLynx, polar_(—)5 min).

Example 241-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-ethanone

1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine(100.00 mg, 0.23 mmol) in a dried 10 mL round-bottom flask was dissolvedin 1.7 mL of methylene chloride and was charged with PS-DIEA (117.95 mg,0.46 mmol). Acetic anhydride (Ac₂O) (11 μL, 0.51 equiv) was added in oneportion. After 15 min., another 5.5 μL of Ac₂O (0.25 equiv) was added.After another 15 min., another 2.64 μL of Ac₂O (0.12 equiv) was added.After another 15 min., another 11 μl of Ac₂O (0.51 equiv) was added. Thereaction was filtered through a fritted funnel, and the resins wererinsed multiple times with methylene chloride. The crude product waspurified by silica gel flash chromatography (wetted with 100% EtOAc,eluted with 5% (7N NH₃) in MeOH/EtOAc) and afforded the desired product;¹H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1 H, d, J=1.68), 8.28 (1 H, d,J=8.20), 8.19 (2 H, dd, J=1.51 Hz, J=1.18), 7.93 (3 H, m), 7.53 (3 H,m), 7.23 (1 H, d, J=5.10), 7.12 (1 H, d, J=5.76), 5.55 (2 H, m), 4.67 (1H, d, J=13.28), 3.83 (1 H, d, J=12.26), 3.06 (1 H, m), 2.96 (2 H, m),2.56 (1 H, m), 2.27 (1 H, m), 2.10 (3 H, s), 1.85 (2 H, t), 1.31 (2 H,m); MS (ES+): m/z 477.11/478.08 (40/20) [MH⁺]; HPLC: t_(R)=2.11 min(OpenLynx, polar_(—)5 min).

Example 251-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-2-methoxy-ethanone

1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine(110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolvedin 2.00 mL of CH₂Cl₂ and charged with PS-DIEA (150 mg, 0.46 mmol).Methoxyacetyl (10 μL, 0.44 equiv) was added in one portion. After 10min., another 10 μL of methoxyacetyl (0.44 equiv) was added. Afteranother 10 min., another 5 μL of methoxylacetyl (0.22 equiv) was added.The reaction was filtered through a flitted funnel, and the resins wererinsed multiple times with CH₂Cl₂. The crude product was purified by a 5g Jones silica gel (wetted with 100% ethyl acetate, eluted with 5% (7NNH₃) in MeOH/EtOAc) and afforded the desired product; ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.41 (1 H, d, J=0.80), 8.35 (1 H, d, 4 J=43.15), 8.23 (2H, m), 7.97 (2 H, m), 7.88 (1 H, dd, J=1.47, 1.73), 7.53 (3 H, m), 7.23(1 H, d, J=5.19), 7.11 (1 H, d, J=5.20), 5.77 (2 H, m), 4.64 (1 H, d,J=13.8), 3.90 (1 H, d, 15.80), 3.49 (2 H, s), 3.50 (3 H, s), 3.04 (1 H,d, J=13.08), 2.97 (2 H, dd, J=2.44, J=2.72), 2.62 (1 H, t), 2.29 (1 H,m), 1.97 (2H, d, J=65.04), 1.37 (2 H, m); MS (ES+): m/z 507.08/508.09(50/30) [MH⁺]; HPLC: t_(R)=2.07 min (OpenLynx, polar_(—)5 min).

Example 263-(1-Methanesulfonyl-piperidin-4-ylmethyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine(110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolvedin 2.00 mL of CH₂Cl₂ and charged with PS-DIEA (150.00 mg, 0.46 mmol).Methanesulfonyl chloride (10 μL, 0.47 equiv) was added in one portion.After 10 min., another 5 μL of methanesulfonyl chloride (0.24 equiv) wasadded. After another 10 min., another 2.1 μL of methanesulfonyl chloride(0.1 equiv) was added. The reaction was filtered through a frittedfunnel, and the resins were rinsed multiple times with CH₂Cl₂. The crudeproduct was purified by 5 g Jones silica gel (wetted with 100% CH₂Cl₂,dry loaded with silica, and eluted with 2% (7N NH₃) in MeOH/CH₂Cl₂→5%(7N NH₃) in MeOH/CH₂Cl₂) and afforded the desired product; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.41 (1 H, d, J=0.85), 8.29 (1 H, d, J=8.86), 8.20(2 H, dd, J=1.51, J=1.12), 7.97 (2 H, m), 7.86 (1 H, dd, J=1.72,J=1.72), 7.53 (4 H, m), 7.24 (1 H, d, J=5.26), 7.08 (1 H, d, J=6.75),3.85 (2 H, d, J=11.88), 2.98 (2 H, d, J=7.08), 2.68 (2 H, t), 2.20 (1 H,m), 1.94 (2 H, d, J=10.92), 1.50 (2 H, m); MS (ES+): m/z 513.02/514.03(80/70) [MH⁺]; HPLC: t_(R)=2.17 min (OpenLynx, polar_(—)5 min).

Example 271-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-2-chloro-ethanone

1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine(110.00 mg, 0.25 mmol) in a dried 15 mL round bottom flask was dissolvedin 2.00 mL of methylene chloride and was charged with PS-DIEA (150 mg,0.46 mmol). Chloroacetyl chloride (10 μL, 0.42 equiv) was added in oneportion. After 10 min., another 5 μL of chloroacetyl chloride (0.21equiv) was added. After another 10 min., another 2.5 μL ofmethoxylacetyl (0.11 equiv) was added. The reaction was filtered througha flitted funnel, and the resins were rinsed multiple times withmethylene chloride. The crude product was purified by a 5 g Jones silicagel (dry loaded with silica, wetted with 100% ethyl acetate and elutedwith 5% NH₃ in MeOH/Ethyl Acetate) and afforded the desired product; ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.74 (1 H, s), 8.30 (1 H, d, J=8.68), 8.21(2 H, d, J=7.01), 7.98 (2 H, m), 7.86 (1 H, dd, J=1.70, J=1.70), 7.53 (3H, m), 7.24 (1 H, d, J=5.34), 7.08 (1 H, d, J=5.31), 4.63 (1 H, d,J=13.24), 3.90 (1 H, d, J=13.2), 3.15 (1 H, t), 2.97 (2 H, d, J=5.64),2.70 (1 H, t), 2.34 (1 H, m), 2.05 (2 H, s), 1.92 (2 H, t), 1.42 (2 H,m); MS (ES+): m/z 511.06/513.02 (50/25) [MH⁺]; HPLC: t_(R)=2.20 min(OpenLynx, polar_(—)5 min).

Example 281-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-2-dimethylamino-ethanone

1-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-2-chloro-ethanone(77.00 mg, 0.15 mmol) was transferred to a pressure reaction vessel anddissolved in 3.15 mL of 2M dimethylamine solution in THF. The reactionwas heated at 80° C. overnight. The crude product was then condensed andpurified by a 5 g Jones silica gel (dry loaded with silica gel; elutedwith 100% CH₂Cl₂→2% (7N NH₃) in MeOH/CH₂Cl₂→5% (7N NH₃) in MeOH/CH₂Cl₂)and afforded the desired product; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.41(1 H, d, J=0.80), 8.28 (1 H, d, J=8.23), 8.19 (2 H, dd, J=2.04, J=1.55),7.93 (3 H, m), 7.53 (3 H, dd, J=1.70, J=1.70), 7.53 (3 H, m), 7.23 (1 H,d, J=5.08), 7.15 (1 H, d, 5.06), 5.52 (2 H, m), 4.63 (1 H, d, J=14.08),4.04 (1 H, d, J=11.88), 2.43 (2 H, q), 2.97 (4 H, d, J=6.08), 2.60 (1 H,t), 2.43 (6 H, s), 2.29 (1 H, m), 1.86 (2 H, d, J=12.96), 1.30 (2 H, m);MS (ES+): m/z 520.11 (5) [MH⁺]; HPLC: t_(R)=1.73 min (OpenLynx,polar_(—)5 min).

Example 294-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylicacid ethylamide

1-(2-Phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine(110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolvedin 2.00 mL of CH₂Cl₂. At four 15 min. increments, 10 μL (0.47 equiv), 5μL (0.24 equiv), 2.1 μL (0.1 equiv) and 2.1 μL (0.1 equiv) ofethylisocyanate were added dropwise, respectfully. The crude product waspurified by 5 g Jones silica gel (wetted with 100% CH₂Cl₂; dry loadedwith silica gel, eluted with 2% (7N NH₃) in MeOH/CH₂Cl₂→5% (7N NH₃) inMeOH/CH₂Cl₂) and afforded the desired product; ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.41 (1 H, d, J=1.64), 8.29 (1 H, d, J=8.38), 8.20 (2 H,dd, J=1.52, J=1.10), 7.97 (2 H, m), 7.87 (1 H, dd, J=1.71, J=1.71), 7.53(4 H, m), 7.24 (1 H, d, J=5.26), 7.08 (1 H, d, J=5.23), 4.38 (1 H, t),3.97 (2 H, d, J=13.44), 3.28 (2 H, m), 2.96 (2 H, d, J=7.12), 2.79 (2 H,t), 2.20 (1 H, m), 1.80 (2 H, d, J=10.60), 1.36 (2 H, m); MS (ES+): m/z506.07/507.08 (50/25) [MH⁺]; HPLC: t_(R)=2.17 min (OpenLynx, polar_(—)5min).

Example 30cis-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol

This compound was prepared utilizing the same procedures as those usedfor Example 1 except3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanolwas used in place of7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline. NMR (400MHz, CDCl₃) δ 8.42 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.0 Hz,211), 7.96-7.92 (m, 3H), 7.58-7.46 (m, 3H), 7.19 (d, J=5.2 Hz, 1H), 7.12(d, J=5.2 Hz, 1H), 5.27 (b, 2H), 4.42 (p, J=7.2 Hz, 1H), 3.36 (p, J=8.0Hz, 1H), 3.02-2.95 (m, 2H), 2.57-2.50 (m, 2H); MS (ES+): m/z 408 (100)[MH⁺].

cis-3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol

An ethanolic suspension (20 mL) of3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanone:(2.5 mmol) was charged with NaBH₄(2.5 mmol) at rt. The reaction mixturewas stirred at rt for 30 min until the reaction solution turned clear.The reaction mixture was quenched by an addition of Na₂SO₄.10 H₂O andconcentrated under reduced pressure. The crude mixture was dissolved inDCM, washed with water (3×15 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.19 (d,J=8.0 Hz, 2H), 7.93-7.87 (m, 3H), 7.58-7.52 (m, 3H), 7.47-7.45 (m, 1H),7.37 (d, J=5.2 Hz, 1H), 4.44 (b, 1H), 3.37 (p, J=8.0 Hz, 1H), 3.03-2.96(m, 2H), 2.60-2.53 (m, 2H); MS (ES+): m/z 427 (100) [MH⁺].

Example 31cis-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-3-yl]-1-methyl-cyclobutanolwas prepared as follows

This compound was prepared utilizing the same procedures as those usedfor Example 1 except3-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanolwas used in place of7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline. ¹H NMR(400 MHz, CDCl₃) δ 8.40 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.19-8.17 (m,2H), 7.92-7.88 (m, 3H), 7.56-7.45 (m, 3H), 7.17 (d, J=4.8 Hz, 1H), 7.11(d, J=5.2 Hz, 1H), 5.29 (b, 2H), 3.46-3.49 (m, 1H), 2.72-2.61 (m, 4H),1.50 (s, 3H); MS (ES+): 422 (M+1).

Additionally,cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanolwas prepared as follows: A solution of3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone(148 mg, 0.36 mmol) in THF (3 mL) at 10° C. was charged with methyllithium and stirred at 10° C. for 10 min. The reaction was quenched withsaturated ammonium chloride and extracted with DCM (3×25 mL). Thecombined DCM layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The crudeproduct was purified by preparative TLC using 5% ethyl acetate inhexanes as eluent to afford the title compound as a yellow solid; MS(ES+): m/z 422.33 [MH⁺]; HPLC: t_(R)=2.09 min (OpenLynx, polar_(—)5min).

Example 32trans-3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol

To a solution of toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo-[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethyl ester (98 mg, 0.165 mmol) in THF (4 mL) at −78° C. was added LAHin THF (0.66 mL, 1 M solution) and the mixture was allowed to warm to 0°C. The reaction was quenched with saturated ammonium chloride solution(1 mL), diluted with DCM (20 mL) and filtered through a pad of celite.The filtrate was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude product was purified by preparativeTLC using 5% methanol in DCM as eluent to afford the title compound as ayellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.42 (t, J=0.6 Hz, 1H), 8.26 (d,J=8.4 Hz, 1H), 8.16-8.19 (m, 2H), 7.90-7.96 (m, 3H), 7.45-7.55 (m, 3H),7.10 (dd, J=6.6, 5.0 Hz, 2H), 5.25 (bs, 2H), 3.88-3.92 (m, 1H),2.60-2.74 (m, 4H), 1.47 (s, 3H); MS (ES+): m/z 422.35 (100) [MH⁺]; HPLC:t_(R)=2.13 min (OpenLynx, polar_(—)5 min).

cis-3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanolwas prepared as follows

3-[8-Chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanonewas dissolved in dry THF (4.0 mL) under N₂ and cooled to −78° C. Asolution of CH₃Li (1 M in Et₂O, 2704, 0.268 mmol) in Et₂O was addedslowly to the cooled solution. The reaction mixture was stirred at −78°C. for 30 min and then allowed to warm to rt over 30 min. The reactionmixture was cooled to 0° C. and quenched by an addition of sat. aq.NH₄Cl solution and the aqueous layer was washed with DCM (3×). Theorganic layers were combined, dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude oil was purified by preparative TLC(silica gel, 1000 gm), developed with EtOAc:hexanes (6:4) andEtOAc:hexanes (7:3), yielding the title compounds as a yellow solid; ¹HNMR (400 MHz, CDCl₃) δ 8.50 (d, J=1.2 Hz, 1H), 8.25 (dd, J=0.8 Hz, 8.0Hz, 1H), 8.19 (td, J=0.8 Hz, 8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 1H), 7.87(s, 2H), 7.56-7.44 (m, 4H), 7.34 (d, J=4.8 Hz, 1H), 3.64 (b, 1H), 3.41(q, J=8.0 Hz, 1H), 2.72-2.63 (m, 4H), 1.50 (s, 3H); MS (ES+): 441 (M+1);HPLC: t_(R)=3.37 min (Openlynx LC-MS, polar_(—)5 min).

Cis &trans-3-[8-Chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol:To a solution of7-[8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline(75 mg, 0.177 mmol) in THF (3 mL) was added mercuric acetate (59 mg,0.185 mmol) and water (3 mL) and the mixture was stirred for 15 min.Sodium hydroxide (2 mL, 3N solution) was added followed by 0.5 N NaBH₄in 3N NaOH (2 mL) and the mixture was diluted with DCM. The aqueouslayer was removed and the DCM layer was filtered through a pad of celiteand evaporated under reduced pressure. The crude product was purified bypreparative TLC using 5% methanol in DCM as eluent to afford cis- andtrans-3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol:

Trans-3-[8-Chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol

¹H NMR (400 MHz, CDCl₃) δ 8.52-8.53 (m, 1H), 8.26 (dd, J=8.5, 0.7 Hz,1H), 8.16-8.19 (m, 2H), 7.89 (d, J=11.6 Hz, 1H), 7.88 (bs, 2H),7.44-7.55 (m, 4H), 7.33 (d, J=4.9 Hz, 1H), 3.88-3.94 (m, 1H), 2.61-2.74(m, 4H), 2.08 (s, 1H), 1.46 (s, 3H); MS (ES+): m/z 441.26 (100) [MH⁺];HPLC: t_(R)=3.42 min (OpenLynx, polar_(—)5 min).

cis-Toluene-4-sulfonic acid3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylester

A solution of3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol(114 mg, 0.25 mmol) in DCM (4 mL) at −30° C. was charged with Et₃N (101mg, 1 mmol) and tosyl chloride (52 mg, 0.275 mmol) and allowed to stirat RT overnight. Water was added to the reaction mixture and extractedwith DCM (3×25 mL). The combined DCM layer was washed with brine, driedover anhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by preparative TLC using 5% ethyl acetate inhexanes as eluent to afford the title compound as a yellow solid; ¹H NMR(400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.18-8.21 (m,2H), 7.85-7.94 (m, 3H), 7.70 (d, J=8.2 Hz, 2H), 7.45-7.55 (m, 4H), 7.33(d, J=4.9 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 4.21 (s, 2H), 3.90-3.95 (m,1H), 2.62-2.71 (m, 4H), 2.27 (s, 3H); MS (ES+): m/z 611.2 (100) [M+];HPLC: t_(R)=3.85 min (OpenLynx, polar_(—)5 min).

Cis & trans methanesulfonic acid3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylester: A solution of3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol(229 mg, 0.50 mmol) in DCM (3 mL) at −30° C. was charged with Et₃N (101mg, 1 mmol) and mesyl chloride (69 mg, 0.6 mmol) and allowed to warm toRT and stir overnight. Water was added to the reaction mixture andextracted with DCM (3×25 mL). The combined DCM layer was washed withbrine, dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by preparative TLC using 5%ethyl acetate in hexanes as eluent to afford the respective cis- andtrans-isomers as yellow solids:

cis-Methanesulfonic acid3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylester

¹H NMR (400 MHz, CDCl₃) δ 8.42 (bs, 1H), 8.21 (d, J=8.6 Hz, 1H),8.09-8.12 (m, 2H), 7.79-7.86 (m, 3H), 7.38-7.49 (m, 4H), 7.31 (d, J=4.9Hz, 1H), 4.40 (s, 2H), 3.91-3.95 (m, 1H), 2.99-3.04 (m, 1H), 2.99 (s,3H), 2.64-2.77 (m, 4H); MS (ES+): m/z 535.19 (100) [M⁺]; HPLC:t_(R)=3.37 min (OpenLynx, polar_(—)5 min).

trans-Methanesulfonic acid3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylester

¹H NMR (400 MHz, CDCl₃) δ 8.43 (bs, 1H), 8.21 (d, J=8.8 Hz, 1H),8.09-8.12 (m, 2H), 7.78-7.87 (m, 3H), 7.41-7.49 (m, 4H), 7.34 (d, J=4.9Hz, 1H), 4.29 (s, 2H), 3.41-3.53 (m, 1H), 3.06 (s, 3H), 2.85-2.90 (m,2H), 2.60-2.65 (m, 2H); MS (ES+): m/z 535.19 (100) [M⁺]; HPLC:t_(R)=3.40 min (OpenLynx, polar_(—)5 min).

Example 333-(3-Methylenecyclobutyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

Ammonia gas was bubbled in to IPA (5 mL, containing 2N NH₃) at −78° C.,till the volume was doubled (10 mL), and this solution was added to aslurry of7-[8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline(500 mg) in IPA (2 mL, containing 2N NH₃) at −78° C. The reactionmixture was heated in a high pressure bomb at 120° C. for 24 h. Thereaction mixture was cooled −78° C. then allowed to warm to rt, dilutedwith DCM (50 mL), washed with saturated sodium bicarbonate, dried overanhydrous sodium sulfate, filtered and evaporated under reduced pressureto afford the title compound as a yellow solid; MS (ES+): m/z 404.34(100) [MH⁺]; HPLC: t_(R)=2.49 min (OpenLynx, polar_(—)5 min).

Example 34 cis-3-[3-(Azidomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine

A solution of{3-[8-amino-1-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methyl4-methylbenzenesulfonate (500 mg, 0.87 mmol) in DMF (10 mL) was chargedwith sodium azide (169 mg, 2.6 mmol), the reaction mixture was stirredat 50° C. overnight. The reaction mixture was diluted with water (10mL), extracted with ethyl acetate (3×30 mL), and the combined organicphases were washed with water (2×30 mL) and brine (30 mL), and dried(Na₂SO₄). The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (JonesFlashmaster, 10 g/70 mL cartridge) (eluting with 100% ethyl acetate),yielding the title compound as an off-white solid; ¹H NMR (400 MHz,CDCl₃) δ 8.42-8.41 (m, 1H), 8.26 (dd, J=8.0 Hz, 0.8 Hz, 1H), 8.21-8.18(m, 2H), 7.97-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.17 (d, J=4.0 Hz, 1H),7.12 (d, J=4.0 Hz, 1H), 5.20 (b, 2H), 3.79-3.71 (m, 1H), 3.40 (d, J=2.8Hz, 1H), 2.92 (dd, J=2.8 Hz, 0.4 Hz, 1H), 2.74-2.69 (m, 3H), 2.46-2.43(m, 2H); MS (ES+): m/z 447.14 (60) [MH⁺]; HPLC: t_(R)=2.48 min(OpenLynx, polar_(—)5 min).

Example 35 cis-3-[3-(Aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine

3-[3-(Azidomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine(0.81 mmol, 360 mg) was dissolved in hot ethanol (15 mL) and chargedwith Lindlar catalyst (0.14 mmol, 362 mg). The reaction mixture waspurged with N₂, evacuated and filled with H₂. The reaction mixture wasstirred under H₂ for 16 h. The suspension was filtered through celiteand the solvent was removed under reduced pressure. Part of the crudematerial (200 mg out of 300 mg) was purified by silica gel flushchromatography (Jones Flashmaster, 5 g/70 mL cartridge) eluting with 3%MeOH (7 N NH₃) in DCM. The final compound was recrystallized from EtOAcand hexane to generate the desired product as a light yellow solid; ¹HNMR (400 MHz, CDCl₃) δ 8.42-8.41 (m, 1H), 8.27 (dd, J=8.0 Hz, 0.4 Hz,1H), 8.21-8.19 (m, 2H), 7.95-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.19 (d,J=4.0 Hz, 1H), 7.11 (d, J=4.0 Hz, 1H), 5.20 (b, 2H), 3.73-3.69 (m, 1H),2.81 (d, J=7.2 Hz, 2H), 2.66-2.62 (m, 2H), 2.58-2.48 (m, 1H), 2.36-2.30(m, 2H); MS (ES+): m/z 421.13 (40) [MH⁺]; HPLC: t_(R)=1.69 min(OpenLynx, polar_(—)5 min).

Example 36cis-N-([3-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methyl)acetamide

A suspension of3-[3-(aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine(0.237 mmol, 100 mg) in DCM (6 mL) was charged with DIEA (0.475 mmol, 83μL) and Ac₂O (0.237 mmol, 22.43 μL) at −40° C. The reaction solution waswarmed to rt slowly and stirred under N₂ for 1.5 h. The reaction wasquenched with water (3 mL), diluted with methylene chloride (20 mL),washed with water (30 mL) and brine (30 mL), and dried (Na₂SO₄). Thefiltrate was concentrated under reduced pressure, and the crude materialwas purified by silica gel flush column chromatography (JonesFlashmaster, 10 g/70 mL cartridge), eluting with 3% MeOH (7 N NH₃) inDCM, yielding the title compound as a light yellow solid. The sample wasrecrystallized from DCM (minimal amount) and EtOAc. The final productwas obtained as an off-white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.43-8.42(m, 1H), 8.28 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.97-7.92(m, 3H), 7.57-7.48 (m, 3H), 7.15 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz,1H), 5.19 (b, 2H), 3.78-3.70 (m, 1H), 3.38 (t, J=5.6 Hz, 2H), 2.77-2.66(m, 3H), 2.42-2.34 (m, 2H), 1.87 (s, 3H); MS (ES+): m/z 463 (100) [MH⁺];HPLC: t_(R)=2.06 min (OpenLynx, polar_(—)5 min).

Example 37cis-N-([3-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methyl)methanesulfonamide

3-[3-(Aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.17 mmol, 70 mg) was dissolved in DCM (4mL), treated with DIEA (1 mmol, 0.742 mL) and then charged with methanesulfonic acid anhydride (0.2 mmol, 34.7 mg) portionwise. The reactionmixture was stirred at rt for 16 h. The reaction was quenched with water(5 mL), diluted with methylene chloride (30 mL), washed with saturatedsodium bicarbonate (40 mL) and brine (40 mL), and dried (Na₂SO₄). Thecrude product was purified by MDP (acidic conditions). The purifiedproduct was dissolved in DCM and washed with saturated aq NaHCO₃ andbrine. The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure, yielding the title compound as a light yellow solid;¹H NMR (400 MHz, CDCl₃) δ 8.42-8.41 (m, 1H), 8.26 (d, J=8.0 Hz, 1H),8.20-8.18 (m, 2H), 7.96-7.91 (m, 3H), 7.56-7.48 (m, 3H), 7.11-7.08 (m,2H), 5.35 (b, 2H), 3.71-3.67 (m, 1H), 3.25 (d, J=6.4 Hz, 1H), 2.94 (s,3H), 2.75-2.63 (m, 3H), 2.39-2.33 (m, 3H); MS (ES+): m/z 499 [MH⁺];HPLC: t_(R)=2.11 min (OpenLynx, polar_(—)5 min).

Example 38cis-3-(4-Methoxy-cyclohexyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

A 2-propanol solution (40 mL) ofcis-8-chloro-3-(4-methoxycyclohexyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin(200 mg, 0.43 mmol) in a parr bomb was cooled to −78° C. Ammonia gas wasbubbled into this solution for 3 min. The bomb was sealed and heated to110° C. for 2 days. After cooled to rt, 2-propanol was removed and thecrude product was purified by silica gel chromatography (70%→100% EtOAcin hexanes) to give the desired product as a yellow solid; ¹H NMR(CDCl₃, 400 MHz) δ 1.58-1.66 (m, 2H), 1.83-1.87 (m, 2H), 2.12-2.28 (m,4H), 3.03-3.11 (m, 1H), 3.36 (s, 3H), 3.55-3.57 (m, 1H), 7.08 (d, J=5.2Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.46-7.56 (m, 3H), 7.90-7.56 (m, 3H),8.18-8.21 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.41 (s, 1H); MS (ES+): m/z450 [MH⁺]; HPLC: t_(R)=2.37 min (OpenLynx, polar_(—)5 min).

Example 39trans-3-(4-Methoxy-cyclohexyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

Prepared according to the procedures described for the synthesis ofcis-3-(4-methoxy-cyclohexyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;¹H NMR (CDCl₃, 400 MHz) δ 1.37-1.47 (m, 2H), 1.91-1.98 (m, 2H),2.15-2.19 (m, 2H), 2.27-2.31 (m, 2H), 2.94-3.00 (m, 1H), 3.27-3.35 (m,1H), 3.48 (s, 3H), 7.10 (d, J=4.8 Hz, 1H), 7.28 (d, J=4.8 Hz, 1H),7.46-7.56 (m, 3H), 7.87-7.97 (m, 3H), 8.18-8.20 (m, 2H), 8.27 (d, J=8.4Hz, 1H), 8.41 (s, 1H); MS (ES+): m/z 450 [MH⁺]; HPLC: t_(R)=2.35 min(OpenLynx, polar_(—)5 min).

7-[8-Chloro-3-(4-methoxy-cyclohexyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenyl-quinoline

A round bottom flask, charged with carbonyldiimidazole (252.2 mg, 1.55mmol) and 4-methoxy-cyclohexanecarboxylic acid (mixture of cis/transisomers) (242.9 mg, 1.54 mmol) was evacuated and filled with nitrogen.THF (15 mL) was added and the reaction mixture was stirred at 60° C. for16 h. (3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methylaminehydrochloride salt (500 mg, 1.10 mmol) was then added and stirring wascontinued at 60° C. for another 20 h. After cooled to rt, the reactionmixture was diluted with 20 mL of EtOAc and washed with sat. NaHCO₃(3×30 mL) followed by brine (3×30 mL). The organic phase was dried overNa₂SO₄, filtered, concentrated under reduced pressure, and purified bysilica gel chromatography (60% EtOAc in hexane 100% EtOAc).N-[(3-Chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamidewas obtained as a yellow solid. To a solution ofN-[(3-chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamide(440 mg, 0.91 mmol) in acetonitrile (20 mL) was added POCl₃ (0.17 mL,1.69 mmol) and DMF (0.3 mL). This mixture was heated to 55° C. under N₂for 2 h, concentrated under reduced pressure, and quenched with 2N NH₃in 2-propanol to pH 9. 2-Propanol was removed under reduced pressure andthe residue was dissolved in dichloromethane (50 mL) and water (30 mL).Layers were separated and the organic phase was washed with brine anddried over Na₂SO₄, filtered, concentrated under reduced pressure, andpurified by silica gel chromatography (2%→6% CH₃CN in dichloromethane)to afford the individual cis-isomer and trans-isomers:

cis-7-[8-Chloro-3-(4-methoxy-cyclohexyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenyl-quinoline

¹H NMR (CDCl₃, 400 MHz) δ 1.59-1.66 (m, 2H), 1.82-1.87 (m, 2H),2.13-2.27 (m, 4H), 3.08-3.16 (m, 1H), 3.35 (s, 3H), 3.56-3.57 (m, 1H),7.35 (d, J=5.2 Hz, 1H), 7.46-7.56 (m, 3H), 7.69 (d, J=5.2, 1H),7.88-7.91 (m, 3H), 7.18-8.20 (m, 2H), 8.26 (dd, J=0.8 Hz, J=8.8 Hz, 1H),8.51 (d, J=1.2 Hz, 1H); MS (ES+): m/z 469 [MH⁺]; HPLC: t_(R)=4.07 min(OpenLynx, polar_(—)5 min).

trans-7-[8-Chloro-3-(4-methoxy-cyclohexyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenyl-quinoline

¹H NMR (CDCl₃, 400 MHz) δ 1.25-1.47 (m, 2H), 1.90-2.01 (m, 2H),2.14-2.17 (m, 2H), 2.27-2.31 (m, 2H), 2.96-3.04 (m, 1H), 3.26-3.35 (m,1H), 3.41 (s, 3H), 7.37 (d, J=4.8 Hz, 1H), 7.44-7.55 (m, 3H), 7.67 (d,J=5.2 Hz, 1H), 7.85-7.91 (m, 3H), 8.16-8.19 (m, 2H), 8.26 (d, J=8.8 Hz,1H), 8.50 (s, 1H); MS (ES+): m/z 469 [MH⁺]; HPLC: t_(R)=4.00 min(OpenLynx, polar_(—)5 min).

Example 403-Cyclobutyl-1-(1-oxy-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

To a cooled (ice-H₂O) solution of7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline(197 mg, 0.48 mmol) in ClCH₂CH₂Cl (20 mL) was added mCPBA (97 mg, max0.43 mmol, max. 77% Aldrich) in one portion. The solution was stirred atthe temperature for 30 min and then allowed to warm to rt by removingthe cooling bath and stirred at rt (2 h). The reaction mixture was againcooled (ice-H₂O) and treated with another portion of mCPBA (107 mg, max0.48 mmol), stirred for 30 min at the temperature and then overnight atrt (15 h). After that time the crude mixture was filtered throughhydromatrix (25 mL) pretreated with 2 M aq NaOH (10 mL). The hydromatrixcolumn was washed with DCM (˜100 mL) and the filtrate was concentratedunder reduced pressure. The resultant yellow residue was purified byflash chromatography on silica gel (70 g cartridge, 0→0.75→4% MeOH inDCM) to yield7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline1-oxide as a yellow gum. A cooled (−10° C.) i-PrOH (15 mL) solution of7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline1-oxide (50 mg) in a Parr bomb was saturated with NH₃(g) for 3 min. Thevessel was sealed and heated at 100-110° C. (bath temperature) for 2 d.The reaction mixture was then cooled to rt, concentrated under reducedpressure and purified by flash chromatography on silica gel (0-4%MeOH+2%˜6 M NH₃ in MeOH. A trituration with hexanes (3×) provided thetitle material as a bright yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 9.12(s, 1H), 8.16 (dd, J=8.2 Hz, 1.8 Hz, 1H), 8.04-7.96 (m, 3H), 7.79 (d,J=8.8 Hz, 1H), 7.57-7.43 (m, 4H), 7.16 (d, J=5.2 Hz, 1H), 7.13 (d, J=4.8Hz, 1H), 5.30 (s, 2H), 3.85 (quintet, J=8.2 Hz, 1H), 2.69-2.60 (m, 2H),2.55-2.50 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.00 (m, 1H); MS (ES+): m/z408.13 (100) [MH⁺]; HPLC: t_(R)=2.14 min (OpenLynx, polar_(—)5 min).

Example 417-Cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine

A flask was charged with7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095mmol),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (38mg, 0.110 mmol), and sodium carbonate (Na₂CO₃) (30 mg, 0.286 mmol) wasevacuated and charged with nitrogen (N₂) (3×). To this mixture wasquickly added tetrakis(triphenylphosphine)palladium(0) and evacuated andcharged with N₂ (2×). This mixture was charged with a previouslydegassed solvent DME/H₂O (5:1) (2 mL) and heated overnight at 75° C. Thereaction mixture was filtered through an autovial (0.45 μM frit) andwashed with MeOH (3×). The filtrate was concentrated in vacuo andpurified by mass directed purification (MDP) resulting in the titlecompound as a pale yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 1.96-2.10 (m,1H), 2.10-2.25 (m, 1H); 2.40-2.56 (m, 2H); 2.60-2.78 (m, 2H); 4.12-4.29(m, 1H); 5.99 (brs, 2H); 7.42-7.58 (m, 3H); 7.84-8.05 (m, 4H); 8.18 (d,J=7.2 Hz, 2H); 8.28 (d, J=8.4 Hz, 1H); 8.39 (s, 1H); MS (ES+): m/z393.14 (100) [MH⁺], HPLC: t_(R)=3.51 min (MicromassZQ, polar_(—)5 min).

Example 427-Cyclobutyl-5-(2-pyridin-2-yl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine

7-Cyclobutyl-5-(2-pyridin-2-yl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylaminewas prepared using the same procedures described as described for7-Cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,except2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolinewas used in place of2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline; ¹HNMR (DMSO-d₆, 400 MHz) S 1.88-2.00 (m, 1H), 2.02-2.16 (m, 1H); 2.32-2.44(m, 2H); 2.44-2.58 (m, 2H); 4.00-4.16 (m, 1H); 6.76 (brs, 2H); 7.45-7.59(m, 1H); 7.94 (s, 1H); 7.94-8.05 (m, 2H); 8.13 (d, J=8.4 Hz, 1H);8.24-8.32 (m, 1H); 8.51-8.68 (m, 3H); 8.72-8.80 (m, 1H); MS (ES+): m/z394.08 (100) [MH⁺], HPLC: t_(R)=3.14 min (MicromassZQ, polar_(—)5 min).

Example 437-Cyclobutyl-5-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine

7-Cyclobutyl-5-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylaminewas prepared using the same procedures described for7-cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,except4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolinewas used in place of2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline and2 equivalents of cesium carbonate was used in place of 3 equivalents ofsodium carbonate; ¹H NMR (CDCl₃, 400 MHz) δ 2.06 (m, 1H), 2.17 (m, 1H);2.47-2.52 (m, 2H); 2.67-2.72 (m, 2H); 2.82 (d, J=0.8 Hz, 3H); 4.14-4.25(m, 1H); 5.78 (brs, 2H); 7.46-7.56 (m, 3H); 7.77 (d, J=0.8 Hz, 1H); 7.92(s, 1H); 7.98 (dd, J=8.6, 1.8 Hz, 1H); 8.15-8.18 (m, 3H); 8.39 (d, J=1.6Hz, 1H); MS (ES+): m/z 407.03 (100) [MH⁺], HPLC: t_(R)=3.54 min(MicromassZQ, polar_(—)5 min).

Example 447-Cyclobutyl-5-(8-fluoro-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine

A stirred solution of7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (40 mg, 0.1mmol),8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline(52 mg, 0.15 mmol) and cesium carbonate (50 mg, 0.15 mmol) indimethoxyethane (DME) (1.67 mL) and H₂O (0.33 mL) was degassed for 10minutes using N₂. Tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006mmol) was added, and the reaction was heated to 75° C. and maintained atthis temperature for 16 hours. After cooling, the reaction mixture waspoured into saturated sodium bicarbonate (NaHCO₃) solution (50 ml) andextracted with EtOAc (3×50 ml). The combined organics were washed withbrine (2×50 ml), dried over magnesium sulfate (MgSO₄), filtered andconcentrated. The material was purified by chromatography on silica gel[eluting with 100% DCM→0.4% MeOH in DCM] resulting in the title compoundas a white solid; ¹H NMR (CDCl₃, 400 MHz) δ 2.06-1.99 (m, 1H), 2.10-2.20(m, 1H), 2.42-2.52 (m, 2H), 2.62-2.71 (m, 2H), 4.14-4.21 (m, 1H),7.45-7.56 (m, 3H), 7.74 (d, J=8.6 Hz, 1H), 7.79 (dd, J=6.3 Hz, 6.3 Hz,1H), 7.87 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.21 (d, J=6.8 Hz, 2H), 8.27(d, J=7.6 Hz, 1H); MS (ES+): m/z 411.00 (100) [MH⁺], HPLC: t_(R)=3.53min (MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine

To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrouspyridine (10 mL) was added phosphorus oxychloride (POCl₃) (0.578 mL,6.20 mmol) and stirred at rt for 15 min. This mixture was dropwisecharged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3Himidazo[5,1f][1,2,4]triazin-4-one (0.653 mg, 2.07 mmol) in anhydrouspyridine (14 mL) and stirred for 1.5 h. The reaction mixture was cooledto 0° C. quenched with 2M NH₃ in isopropanol (IPA) until basic thenallowed to reach it and stirred for an additional 2 h. The reactionmixture was filtered through a fritted Buchner funnel and washed withDCM. The filtrate was concentrated in vacuo and purified bychromatography on silica gel [eluting with 30% EtOAc in DCM] resultingin the title compound as an off-white solid; ¹H NMR (CDCl₃, 400 MHz) δ1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m,2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH⁺],HPLC: t_(R)=2.59 min (MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-5-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one

A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789mg, 4.15 mmol) and N-iodosuccinimide (933 mg, 4.15 mmol) in anhydrousDMF (40 mL) was stirred overnight at rt. An additional 4 equiv of NISwas added and reaction was heated to 55° C. for 6 h. The reactionmixture was concentrated in vacuo and partitioned between DCM and H₂Oand separated. The aqueous layer was washed with DCM (3×) and thecombined organic fractions were washed with 1M sodium thiosulfate(Na₂S₂O₃) (1×), brine (1×), dried over sodium sulfate (Na₂SO₄),filtered, and concentrated in vacuo. The solid was triturated with 20%EtOAc in DCM and filtered through a fitted Buchner funnel resulting inthe title compound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m,1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH⁺], HPLC: t_(R)=2.62min (MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

A crude solution of cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-amide (1.33 g, 6.39 mmol)in phosphorus oxychloride (POCl₃) (10 mL) was heated to 55° C. Thereaction was heated for 2 h then concentrated in vacuo and the crude oilwas cooled to 0° C. in an ice-bath and quenched with 2 M NH₃ inisopropanol (IPA) until slightly basic. This crude reaction mixture wasconcentrated in vacuo and was partitioned between DCM and H₂O andseparated. The aqueous layer was extracted with DCM (3×) and thecombined organic fractions were dried over sodium sulfate (Na₂SO₄),filtered and concentrated in vacuo. The crude material was purified bychromatography on silica gel [eluting with 5% MeOH in DCM], resulting inthe title compound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m,1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z191.27 (100) [MH⁺], HPLC: t_(R)=2.06 min (MicromassZQ, polar_(—)5 min).

Cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-amide

To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96mmol) and N,N-diisopropylethylamine (DIEA) (0.829 mL, 4.76 mmol) inanhydrous N,N-dimethylfomamide (DMF) (20 mL) and anhydrous pyridine (2mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL,3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5h. The reaction mixture was quenched with H₂O (2 mL) and concentrated invacuo and was purified by chromatography on silica gel [eluting with 5%MeOH in DCM (200 mL)→10% MeOH in DCM (800 mL)], affording the titlecompound; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m,1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d,2H); 7.97 (brt, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100)[MH⁺], HPLC: t_(R)=1.56 min (MicromassZQ, polar_(—)5 min).

6-Aminomethyl-4H-[1,2,4]triazin-5-one

A slurry of2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione (4g, 15.6 mmol) in DCM/EtOH (1:1) (150 mL) was charged with anhydroushydrazine (1.23 mL, 39.0 mmol) and stirred at it for 18 h. The reactionmixture was concentrated in vacuo and the off-white solid was trituratedwith warm CHCl₃ and filtered through a fritted funnel. The solid wasthen triturated with hot boiling methanol (MeOH) and filtered through aflitted funnel resulting in an off-white solid. The material wastriturated a second time as before and dried overnight resulting in thetitle compound as a white solid, which was taken on to the next stepwithout further purification; ¹H NMR (DMSO-d₆, 400 MHz) δ 3.88 (s, 2H),8.31 (2, 1H); MS (ES+): m/z 127.07 (100) [MH⁺], HPLC: t_(R)=0.34 min(MicromassZQ, polar_(—)5 min).

2-(5-Oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione

A slurry of2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione(1.0 g, 3.47 mmol) in EtOH (40 mL) was charged with excess

Raney Ni (3 spatula) and heated to reflux for 2 h. The reaction mixturewas filtered hot through a small pad of celite and washed with a hotmixture of EtOH/THF (1:1) (100 mL) and the filtrate was concentrated invacuo resulting in the title compound as an off-white solid; ¹H NMR(DMSO-d₆, 400 MHz) δ 4.75 (s, 2H), 7.84-7.98 (m, 4H), 8.66 (s, 1H); MS(ES+): m/z 257.22 (100) [MH⁺], HPLC: t_(R)=2.08 min (MicromassZQ,polar_(—)5 min).

2-(5-Oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)-indan-1,3-dione

A slurry of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-oxo-propionic acidethyl ester (20 g, 76.6 mmol) in anhydrous EtOH (300 mL) was chargedwith thiosemicarbazide (6.98 g, 76.6 mmol) in one portion and heated to80° C. for 2 hr. The reaction mixture was charged withN,N-diisopropylethylamine (DIEA) (26.7 mL, 76.56 mmol) and heated to 40°C. for 6 h then stirred at rt for an additional 10 h. The reactionmixture was concentrated in vacuo and solid was triturated with hotEtOH/EtOAc filtered and washed with EtOAc. The solid was dried overnightin a vacuum oven (40° C.) resulting in the title compound as anoff-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 4.68 (s, 2H), 7.85-7.95 (m,4H); MS (ES+): m/z 289.2 (100) [MH⁺], HPLC: t_(R)=2.50 min (MicromassZQ,polar_(—)5 min).

Example 457-Cyclobutyl-5-(2-phenylquinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A flask equipped with a reflux condenser was charged with2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (67mg, 0.20 mmol), 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(64 mg, 0.20 mmol) and Na₂CO₃ (56 mg, 0.51 mmol). The reaction setup wasevacuated and refilled with Ar (3×). Pd(PPh₃)₄ (24 mg, 0.021 mmol) wasadded swiftly minimizing exposure to air and the system was evacuatedand refilled with Ar (3×) again. Degassed solvent mixture H₂O-DMF (1:5v/v, 5 mL) was added and the reaction mixture was heated at 80° C. for42 h. The resulting orange-light brown solution was partitioned betweenDCM (˜80 mL) and H₂O (10 mL). The aqueous layer was extracted with DCM(3×). Combined organics were washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure (125 mg). Purification by flashchromatography (silica gel, 25 g, 0-2% MeOH in DCM) provided the titlecompound as a pale yellow solid; The material was also later triturated(hexane 2×, Et₂O 1×); ¹H NMR (400 MHz, CDCl₃) δ 9.46 (d, J=0.8 Hz, 1H),8.65-8.58 (m, 2H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=8.4 Hz, 1H),7.75 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.39 (s, 1H), 5.44(br, 2H), 5.33 (quintet, J=8.2 Hz, 1H), 2.67-2.40 (m, 4H), 2.17-1.89 (m,2H). MS (ES+): m/z 393.1 (100) [MH⁺]; HPLC: t_(R)=2.91 min (OpenLynx,polar_(—)5 min).

Example 463-Cyclobutyl-1-(4-methoxy-2-phenylquinazolin-7-yl)imidazo[1,5-a]pyrazin-8-amine

Synthesized as7-cyclobutyl-5-(2-phenylquinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminefrom (78 mg, 0.25 mmol) of3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine. The crude material waspurified flash chromatography on silica gel (70 g cartridge, 0-2% MeOHin DCM) followed by recrystallization (EtOAc-hexanes) and trituration(Et₂O). Purification of the mother liquor by HPLC provided more of thetitle compound (a light orange solid); ¹H NMR (400 MHz, CDCl₃) δ8.65-8.60 (m, 2H), 8.31-8.25 (m, 2H), 7.94 (dd, J=1.6 Hz, 8.0 Hz, 1H),7.57-7.48 (m, 3H), 7.18 (d, J=5.2 Hz, 1H), 7.13 (d, J=4.8 Hz, 1H), 5.18(br, 2H), 4.34 (s, 3H), 3.86 (quintet, J=8.6 Hz, 1H), 2.75-2.60 (m, 2H),2.58-2.47 (m, 2H), 2.26-2.12 (m, 1H), 2.11-2.00 (m, 1H). MS (ES+): m/z423.0 (100) [MH⁺]; HPLC: t_(R)=2.62 min (OpenLynx, polar_(—)5 min).

Example 473-Cyclobutyl-1-(4-methyl-2-phenyl-quinazolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

Synthesized as7-cyclobutyl-5-(2-phenylquinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminefrom of 1-bromo-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine (16 mg, 0.06mmol). Crude material was purified by preparative TLC (silica gel, 5%MeOH in DCM) followed by a recrystallization (EtOAc) and trituration(hexanes) to afford the title compound as a light yellow solid; MS(ES+): m/z 407.1 (100); HPLC: t_(R) (min) 2.44 (OpenLynx, polar_(—)5min).

Example 483-Cyclobutyl-1-(3-phenylquinoxalin-6-yl)imidazo[1,5-a]pyrazin-8-amine

DCM solution of7-(8-chloro-3-cyclobutyl-7,8-dihydroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoxaline(61 mg, 0.15 mmol) was evaporated to dryness by passing a stream of N₂.The residue was suspended in anh. i-PrOH (4 mL) and the suspension wassaturated with gaseous NH₃ at 0° C. (2 min). The reaction vessel wassealed and heated to 100° C. (external temperature) for 63 h. Then thereaction was cooled to rt, concentrated under reduced pressure andpurified by flash chromatography (silica gel, 0-5% MeOH in DCM) and thenpreparative TLC (4% MeOH in CH₃CN) to afford the title compound as alight yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 9.36 (d, J=4Hz, 1H), 8.43(s, 1H), 8.30-8.25 (m, 4H), 7.65-7.50 (m, 3H), 7.15 (m, 2H), 5.26 (br,2H), 3.86 (quintet, J=8 Hz, 1H), 2.75-2.60 (m, 2H), 2.60-2.45 (m, 2H),2.20 (q, J=8 Hz, 1H), 2.07 (br, 1H). MS (ES+): m/z 393.1 (100) [MH⁺];HPLC: t_(R)=2.30 min (OpenLynx, polar_(—)5 min).

7-(8-Chloro-3-cyclobutyl-7,8-dihydroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoxaline

N-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-cyclobutanecarboxamide(56 mg, 0.13 mmol) was heated in POCl₃ (5 mL) under Ar at 70° C. for 26h. Later the reaction was cooled to rt, evaporated under reducedpressure and then high vacuum. A solution of NH₃ in i-PrOH (2 M, 10 mLwas added to the crude material cooled in an ice-H₂O bath under Ar. Themixture was stirred, sonicated and filtered. The solids and the reactionflask were washed with i-PrOH multiple times. The filtrate wasconcentrated under reduced pressure. The light yellow residue waspartitioned between DCM (60 mL) and H₂O (20 mL). The aq. layer wasextracted with DCM (2×). Combined organic phase was washed with brineand dried (Na₂SO₄) to afford the title compound as a light yellow solid;¹H NMR (400 MHz, CD₃CN) δ 9.40 (s, 1H), 8.36 (s, 1H), 8.32-8.25 (m, 2H),8.13-8.11 (m, 2H), 7.77 (d, J=4.8 Hz, 1H), 7.63-7.51 (m, 3H), 7.32 (d,J=4.8 Hz, 1H), 3.97 (qund, J=1.2 Hz, 8.4 Hz, 1H), 2.60-2.45 (m, 4H),2.05-1.95 (m, 2H). MS (ES+): m/z 412.0 (40) [MH⁺]; HPLC: t_(R)=4.10 min(OpenLynx, polar_(—)5 min).

N-[(3-Chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]cyclobutanecarboxamide

(3-Chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl-amine (106 mg,0.30 mmol) and cyclobutanecarboxylic acid (51 mg, 0.46 mmol) weredissolved in DCM (10 mL). EDC (93 mg, 0.49 mmo) and HOBt hydrate (62 mg,0.46 mmol) were added in sequence followed by N,N-diisopropylethylamine(0.15 mL, 0.83 mmol). The reaction was stirred at rt under Ar for 24 hthen evaporated to dryness and purified by flash chromatography (0-1.5%MeOH in DCM) to afford a reddish oil. The material was dissolved in DCM(50 mL), washed with satd NaHCO₃ (2×), H₂O (1×), brine (1×), dried(MgSO₄) and concentrated under reduced pressure (light yellow oil).Purification by flash chromatography (silica gel, 33% to 65% EtOAc inhexanes) afforded the title compound as a white solid; ¹H NMR (400 MHz,CD₃CN) δ 9.40 (s, 1H), 8.60 (d, J=2.8 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H),8.30-8.25 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.80 (dd, J=2.0Hz, 8.8 Hz, 1H), 7.85-7.75 (m, 3H), 7.51 (d, J=7.8 Hz, 1H), 6.77 (d,J=8.0 Hz, 1H), 3.20 (quintet, J=8.4 Hz, 1H), 2.25-2.05 (m, 4H),1.85-1.75 (m, 2H).). MS (ES+): m/z 430.0 (100) [MH⁺]; HPLC: t_(R)=3.40min (OpenLynx, polar_(—)5 min).

(3-Chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methylamine

A flask containing crude(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methanol (153 mg, ˜0.44mmol) was flashed with Ar and charged with phthalimide (71 mg, 0.48mmol) and triphenylphosphine (130 mg, 0.48 mmol) and anh. THF (10 mL).DIAD (0.1 mL, 0.48 mmol) was added slowly dropwise at rt and then thereaction was stirred at rt for 16 h. The reaction was concentrated underreduced pressure and purified by flash chromatography (silica gel, 5%EtOAc in DCM to 10%) affording2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dionecompound as a creamy solid. To stirred solution of the crude2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione(147 mg, 0.31 mmol) in anh. EtOH (12 mL) and anh. DCM (2 mL) under Arwas added anh. hydrazine (0.03 mL, 0.9 mmol). The reaction mixture wasstirred at rt for 22 h. The 1:1 mixture of the product and a partiallycleaved phthalimide was concentrated under reduced pressure at rt anddried under high vacuum overnight. The light yellow, solid residue wasdissolved in anh. i-PrOH (6 mL) and anh. CHCl₃ (3 mL) and heated underAr at 50° C. for 16 h. Later the reaction was cooled to rt, evaporatedto dryness and triturated with DCM. The DCM aliquots were filteredthrough a pad of Celite affording the title compound as a light yellowsolid; ¹H NMR (400 MHz, CD₃OD/CDCl₃) δ 9.37 (s, 1H), 8.71 (d, J=2.4 Hz,1H), 8.39 (d, J=2.4 Hz, 1H), 8.23 (d, J=6.8 Hz, 2H), 8.12 (s, 1H), 8.06(d, J=8.4 Hz, 1H), 7.88 (dd, J=0.8 Hz, 8.8 Hz, 1H), 7.62-7.52 (m, 3H),5.81 (s, 1H). MS (ES+): m/z 348.0 (40) [MH⁺]; HPLC: t_(R)=2.08 min(OpenLynx, polar_(—)5 min).

3-Chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methanol

To a stirred, THF (3.5 mL) solution of TMP (0.11 mL, 0.62 mm) at −8° C.was added n-BuLi (1.6 M in hexanes, 0.36 mL, 0.58 mmol) dropwise. Afterstirring at −15 to −8° C. (external temperatures) for 10 min the mixturewas cooled to −78° C. and chloropyrazine (64 mg, 0.58 mmol) was addeddropwise as a solution in THF (0.2 mL) over 8 min. The flask containingthe reagent was rinsed with more THF (0.1 mL) and the rinse was added tothe reaction over 5 min. The resultant orange-brown mixture was stirredfor 20 min and later was treated with 3-phenylquinoxaline-6-carbaldehyde(112 mg, 0.48 mmol) in THF (1.5 mL) (dropwise addition over 20 min). Thereaction mixture was stirred at −75° C. (external temperature) for 2 h.Later, 0.25 M aq citric acid (10 mL) was added in one portion and thereaction was allowed to warm to rt after an immediate removal of thecooling bath. The reaction was shaken intermittently to improvestirring. Extraction with EtOAc (3×), washing (satd NaHCO₃, brine) anddrying (Na₂SO₄) provided crude material which was purified by flashchromatography (SiO₂, 0-100% EtOAc in DCM) to afford the title compound.MS (ES+): m/z 349.0 (100) [MH⁺]; HPLC: t_(R)=3.10 min (OpenLynx,polar_(—)5 min).

3-Phenylquinoxaline-6-carbaldehyde

DIBAL (1.0 M in THF, 2.0 mL, 2.0 mmol was added to a THF (5 mL) solutionof N-methoxy-N-methyl-3-phenylquinoxaline-6-carboxamide (198 mg, 0.67mmol) under N₂ over 10 min at −78° C. The reaction was stirred for 2.5 hat the temperature, then satd solution of potassium sodium tartrate(Rochelle salt), was added. The cooling bath was removed immediatelyafter the addition. The reaction was stirred for 30 min turning into aclear orange solution. The crude mixture was extracted with DCM (3×),washed (satd Rochelle salt, brine), dried, concentrated and purified byflash chromatography (SiO₂, 0-1.5% MeOH in DCM) to afford the titlecompound as a white solid; ¹H NMR (400 MHz, CDCl₃) δ 10.27 (s, 1H), 9.43(s, 1H), 8.63 (s, 1H), 8.26-8.20 (m, 4H), 7.65-7.52 (m, 3H). MS (ES+):m/z 235.1 (100) [MH⁺]; HPLC: t_(R)=3.38 min (OpenLynx, polar_(—)5 min).

N-Methoxy-N-methyl-3-phenylquinoxaline-6-carboxamide

A suspension of the 3-nitro-4-[(2-oxo-2-phenylethyl)-amino]benzoic acid(889 mg, 3.0 mmol), Pd—C (10% in Pd, 50% in H₂O, 315 mg, 0.15 mmol) inDMF (25 mL) and MeOH (5 mL) was shaken at rt under H₂ (3.3 atm) for 22h. The reaction mixture was filtered through Celite. The Celite layerwas washed with MeOH multiple times. The filtrate was evaporated todryness and the resultant solid was triturated with hot MeOH to affordthe title compound as a grey solid. The rest of the material wasrecrystallized from EtOH affording more of3-phenylquinoxaline-6-carboxylic acid. To a stirred solution3-phenylquinoxaline-6-carboxylic acid (4736-68, 217 mg, 0.87 mmol) inanh. THF (18 mL) was added CDI (212 mg, 1.3 mmol) in one portion at it.The reaction was heated at 55° C. for 2 h then cooled to it and treatedin sequence with N,N-diisopropylethylamine (0.47 mL, 2.6 mmol) andMe(MeO)NH*HCl (248 mg, 2.6 mmol). The reaction was stirred at rt for 20h. THF was removed by evaporation under reduced pressure. The resultantresidue was dissolved in DCM, washed (H₂O (2×), brine), dried (Na₂SO₄)and concentrated under reduced pressure to afford the title material asan off-white solid; ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.46 (d,J=2.0 Hz, 1H), 8.22-8.15 (m, 2H), 8.12 (d, J=8.8 Hz, 1H), 7.98 (dd,J=1.6 Hz, 8.4 Hz, 1H), 7.60-7.50 (m, 3H), 3.57 (s, 3H), 3.42 (s, 3H). MS(ES+): m/z 294.1 (100) [MH⁺]; HPLC: t_(R)=3.03 min (OpenLynx, polar_(—)5min).

3-Nitro-4-[(2-oxo-2-phenylethyl)amino]benzoic acid

A DCM (50 mL) suspension of4-[(2-hydroxy-2-phenylethyl)amino]-3-nitrobenzoic acid (1.0 g, 3.3 mmol)was treated with Dess-Martin periodinane reagent (1.5 g, 3.5 mmol) at rtin one lot. The reaction mixture was stirred at rt for 2 h. The solidwas filtered off and washed with DCM to afford the title compound as ayellow solid; ¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (br, 1H), 9.08 (t, J=4.4Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.14 (d, J=8.0 Hz, 2H), 8.01 (dd, J=1.6Hz, 8.8 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 2H), 7.23(d, J=8.8 Hz, 1H), 5.14 (d, J=4.8 Hz, 2H). MS (ES+): m/z 301.1 (40)[MH⁺]; HPLC: t_(R)=3.10 min (OpenLynx, polar_(—)5 min).

4-[(2-hydroxy-2-phenylethyl)amino]-3-nitrobenzoic acid

A flask, containing 4-fluoro-3-nitrobenzoic acid (8.00 g, 43.2 mmol) and2-amino-1-phenylethanol (8.89 g, 64.8 mmol) dissolved in EtOH (80 mL),was purged with N₂. Anh. N,N-diisopropylethylamine (19 mL, 108 mmol) wasadded and the reaction mixture was heated at reflux for 24 h. Later thereaction was cooled to rt and concentrated under reduced pressure. Thesolid residue was dissolved in EtOAc, washed (1 M aq HCl (3×), H₂O (2×),brine), dried (Na₂SO₄) and evaporated to dryness to afford the titlecompound as a bright yellow solid; ¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (s,1H), 8.67 (t, J=5.2 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 7.92 (ddd, J=0.4Hz, 2.0 Hz, 9.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (t, 7.2 Hz, 2H),7.28 (tt, J=1.2 Hz, 6.8 Hz, 1H), 7.18 (d, J=9.2 Hz, 114), 5.89 (d, J=4.4Hz, 1H), 4.91 (q, J=3.6 Hz, 1H), 3.72-3.63 (m, 1H), 3.53-3.45 (m, 1H).MS (ES+): m/z 285.1 (100) [MH⁺-18]; HPLC: t_(R)=2.80 min (OpenLynx,polar_(—)5 min).

Example 493-[3-(4-Methyl-piperazin-1-yl)-cyclobutyl]-1-(2-phenyl-4-trifluoromethyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

1-Iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine(120 mg, 0.00029 mole),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline(230 mg, 0.00058 mole), cesium carbonate (330 mg, 0.0010 mole),1,2-dimethoxyethane (6 mL, 0.06 mole) and water (1 mL) were combined ina 25 ml round bottom flask with a magnetic stir bar. The flask wassubjected to three vacuum, argon cycles and charged withtetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000030 mole). Theflask was subjected to three vacuum, argon cycles again. The reactionwas stirred under argon at 75° C. (external temperature) overnight. Theproduct mixture was concentrated in vacuo, then allowed to stand undervacuum for 1 h. The product mixture was then chromatographed on silicagel with methylene chloride, methanol, concentrated ammonium hydroxide(140:10:1). Only the purest fractions were combined and concentration invacuo, and placement under high vacuum for 30 minutes afforded the titlecompound as a yellow solid. The solid was re-crystallized fromhexanes/ether to afford the title compound as a yellow solid; 1H NMR(CD₃OD, 400 MHz) δ 2.14-2.62 (m, 15 H), 2.78-2.82 (Q, 1 H, J=7.9 Hz),3.62-3.67 (Q, 1H, J=7.9 H), 6.32 (bs, 2 H), 7.12-7.14 (d, 1 H, J=4.8Hz), 7.58-7.64 (m, 4 H), 8.16-8.22 (m, 2 H), 8.39-8.42 (m, 3 H), 8.48(s, 1 H); ¹⁹F NMR (DMSO, 400 MHz) δ-60.15; MS (ES+): 557.98 (10) [MH+];HPLC T_(R) 3.408 min. (100%) (polar_(—)15 min).

Example 503-Cyclobutyl-1-(2-pyridin-4-ylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine

N₂ was bubbled into a stirred mixture of1-bromo-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine (48 mg, 0.18 mmol),2-pyridin-4-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline(90 mg, 0.27 mmol), Pd(PPh₃)₄ (12.5 mg, 0.0108 mmol), and Na₂CO₃ (48 mg,0.45 mmol) in DMF/H₂O (5/1, 6 mL) for 5 min. This mixture was thenstirred at 80° C. under N₂ for 40 h. The solvents were removed; theresidue was dissolved in MeOH and submitted to the mass-directedpurification system and provided the desired product; ¹H-NMR (CDCl₃, 400MHz) δ 2.02-2.10 (m, 1 H), 2.17-2.24 (m, 1 H), 2.50-2.57 (m, 2 H),2.62-2.70 (m, 2 H), 3.84-3.89 (m, 1 H), 5.45 (s, br, 2 H), 7.10 (d,J=4.4 Hz, 1 H), 7.17 (d, J=5.2 Hz, 1 H), 7.96 (d, J=8.8 Hz, 1 H),8.00-8.01 (m, 2 H), 8.10 (d, J=6.0 Hz, 2 H), 8.35 (d, J=8.4 Hz, 1 H),8.45 (s, 1 H), 8.80 (d, J=4.8 Hz, 2 H); MS (ES+): m/z 393 [MH⁺]; HPLC:t_(R)=1.94 min (OpenLynx, polar_(—)5 min).

Example 513-Cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

The mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-ylamine (62.8mg 0.200 mmol),2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline(79.1mg, 1.2 eq.), Pd(PPh₃)₄ (14.0 mg, 6% eq.) and Na₂CO₃ (53.0 mg, 2.5 eq.)in DMF (5 ml)/H₂O (1 ml) was flushed with N₂ for 30 min at rt and heatedat 80° C. for 16 h under N₂. After that time, the reaction mixture wastreated with H₂O (20 ml), and was then extracted with CH₂Cl₂ (2×25 ml).The extracts were washed with H₂O (2×20 ml), and dried over MgSO₄. Afterthe solid was filtered off and the solvent was removed in vacuo, thecrude yellow oil (105 mg) was purified by MS directed purificationsystem to obtain a yellow solid of3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;¹H NMR (CDCl₃, 400 MHz) δ 2.05-2.09 (m, 1 H), 2.15-2.22 (m, 1 H),2.48-2.56 (m, 2 H), 2.62-2.72 (m, 2 H), 3.85 (quintet, 1 H, J=8.4 Hz),5.27 (s, 2H), 7.09-7.10 (d, 1 H, J=4.8 Hz), 7.15-7.16 (d, 1 H, J=4.8Hz), 7.36-7.39 (m, 1 H), 7.86-7.90 (m, 1 H), 7.97 (m, 2 H), 8.31-8.33(d, 1 H, J=8.8 Hz), 8.43 (s, 1 H), 8.59-8.61 (d, 1 H, J=8.8 Hz),8.67-8.69 (d, 1 H, J=7.6 Hz), 8.75-8.76 (d, 1 H, J=4.0 Hz); MS (ES+):393.4 (M+1), t_(R)(polar-5 min)=2.2 min.

Example 523-Cyclobutyl-1-(2-pyridin-3-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

Prepared according to the procedures above for3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;¹H NMR (CDCl₃, 400 MHz) δ 2.03-2.11 (m, 1 H), 2.14-2.23 (m, 1 H),2.49-2.56 (m, 2 H), 2.57-2.72 (m, 2 H), 3.82-3.91 (quintet, 1 H, J=8.4Hz), 5.18 (s, 2 H), 7.11-7.12 (d, 1 H, J=4.8 Hz), 7.17-7.18 (d, 1 H,J=4.8 Hz), 7.46-7.49 (m, 1 H), 7.92-7.94 (d, 1 H, J=8.4 Hz), 7.98-7.99(m, 2 H), 8.31-8.33 (dd, 1 H, J=0.4 & 8.4 Hz), 8.44 (t, 1 H, J=0.8 Hz),8.54-8.57 (m, 1 H), 8.71-8.73 (dd, 1 H, J=1.6 & 4.8 Hz), 9.38 (dd, 1 H,J=0.8 & 2.4 Hz); MS (ES+): 393.3 (M+1); t_(R)(polar-5 min)=2.0 min.

Example 53Cyclobutyl-1-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine

To a mixture of 3-cyclobutyl-1-iodo-imidazo[1,5-a]pyrazin-8-ylamine (80mg, 0.23 mmol),4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(100 mg, 0.30 mmol) and base (Na₂CO₃ (74 mg, 0.70 mmol) under Ar wasadded Pd(PPh₃)₄ (14 mg, 0.013 mmol) with minimum exposure to air. Theflask was then evacuated and refilled with Ar before the degassed DME(2.2 mL) and H₂O (0.5 mL) were added. The reaction was heated at 80° C.for 27 h, concentrated under reduced pressure and purified by SPE(MP-TsOH, 500 mg 6 mL, Argonaut lot 31562735HA) loading as a DCMsuspension and eluting with 2 M NH₃ in MeOH to afford crude materialwhich was purified by preparative HPLC to afford the title compound as alight yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=2.0 Hz, 1H),8.21-8.15 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.4 Hz, 2.0 Hz,1H), 7.76 (d, J=−0.8 Hz, 1H), 7.57-7.45 (m, 3H), 7.17 (d, J=4.8 Hz, 1H),7.10 (d, J=4.8 Hz, 1H), 5.19 (s, 2H), 3.88 (quintet, J=8.4 Hz, 1H), 2.81(s, 3H), 2.72-2.61 (m, 2H), 2.57-2.48 (m, 2H), 2.26-2.12 (m, 1H),2.11-2.02 (m, 1H); MS (ES+): m/z 406.2 (75) [MH⁺]; HPLC: t_(R)=2.38 min(OpenLynx, polar_(—)5 min).

Cis- and trans-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester were prepared as follows: A suspension of{3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol(125 mg, 0.3 mmol) in dry methylene chloride (5 mL) and pyridine (2 mL)was charged with a solution of Ts₂O (108 mg, 0.33 mmol) in methylenechloride (1 mL) at −40° C. under N₂ atmosphere. The mixture was slowlywarmed to rt overnight. The reaction was quenched with water (1 mL),diluted with methylene chloride (40 mL), washed with sat. aq. NaHCO₃(2×10 mL) and brine (2×10 mL), and dried over anhydrous sodium sulfate.The filtrate was concentrated under reduced pressure, and the crudematerial was purified by silica gel column chromatography (eluting with100% ethyl acetate→EtOAc:MeOH=98:2→96:4) to obtain the individual titlecompounds as a light yellow solid.

Example 54 cis-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester

MS (ES+): m/z 576 [MH⁺]; ¹H NMR (CDCl₃, 400 MHz) δ 2.31-2.37 (m, 2H),2.40 (s, 3H), 2.58-2.66 (m, 2H), 2.82 (m, 1H), 3.73 (m, 1H), 4.10 (d,J=6.7 Hz, 2H), 5.23 (br s, 2H, NH₂), 7.08-7.13 (m, 2H), 8.31 (d, J=8.1Hz, 2H), 7.46-7.56 (m, 3H), 7.79 (d, J=8.3 Hz, 2H), 7.90-7.97 (m, 3H),8.19-8.21 (m, 2H), 8.28 (d, J=8.5 Hz, 1H), 8.40 (s, 1H).

Example 55 trans-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester

¹H NMR (400 MHz, CDCl₃) δ 8.41 (t, J=0.8 Hz, 1H), 8.26 (d, J=8.8 Hz,1H), 8.20-8.17 (m, 2H), 7.94-7.91 (m, 3H), 7.84 (d, J=8.0 Hz, 2H),7.54-7.47 (m, 3H), 7.37 (d, J=8.0 Hz, 2H), 7.10 (d, J=5.2 Hz, 1H), 7.06(d, J=4.8 Hz, 1H), 5.27 (b, 2H), 4.20 (d, J=6.0 Hz, 2H), 3.80 (p, J=4Hz,1H), 2.88-2.81 (m, 1H), 2.77-2.70 (m, 2H), 2.46 (s, 3H), 2.43-2.30 (m,2H); MS (ES+): m/z 576 (100) [MH⁺].

Example 56{3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol

A solution of{3-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol(compound of Formula II-B where Z=cyclobutyl andQ¹=2-phenylquinolin-7-yl) (265 mg, 0.6 mmol) in 5 mL of ^(i)PrOH wascooled to −78° C. and charged with NH₃ gas for 1 min. This sealed tubewas equipped with a teflon O-ring, sealed and heated at 110° C. for 3days. The mixture was cooled to −78° C. and the cap was removed. Thesalt was filtered off and the filtrate was concentrated under reducedpressure. The crude material was purified by silica gel columnchromatography (eluting with 100% ethyl acetate→EtOAc:MeOH=90:10) toobtain the title compound as a light yellow solid, a mixture of cis andtrans isomers in the ratio of 5:1; MS (ES+): m/z 422 [MH⁺]; ¹H NMR(CDCl₃, 400 MHz): δ=2.42-2.48 (m, 2H), 2.66-2.74 (m, 3H), 3.71-3.85 (m,3H), 5.25 (br s, 2H), 7.10-7.19 (m, 2H), 7.46-7.57 (m, 3H), 7.91-7.97(m, 3H), 8.18-8.21 (m, 213), 8.27 (d, J=8.6 Hz, 1H), 8.42, 8.44 (2×s,1H, 5:1 ratio).

Example 57cis-{3-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol

A 2-propanol solution (200 mL) ofcis-3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl4-nitrobenzoate (20 g, 33.9 mmol) in a parr bomb was cooled to −78° C.Ammonia gas was bubbled into this solution for 8 min. The bomb wassealed and heated at 110° C. for 5 days. After cooled to rt, solidprecipitates were collected by filtration and washed with water multipletimes. The solid was dried in a vacuum oven overnight, affording thedesired product. The filtrate was concentrated and the crude product waspurified by silica gel chromatography (100% EtOAc→5% MeOH in EtOAc 10%MeOH in EtOAc) to afford another batch of the title compound; ¹H NMR(DMSO-d₆, 400 MHz) δ 2.15-2.25 (m, 2H), 2.43-2.50 (m, 2H, overlap withsignal of DMSO), 3.43 (s, 2H), 3.78-3.86 (m, 1H), 4.54 (t, J=5.2 Hz 1H),6.28 (br s, 2H), 7.09 (d, J=4.8 Hz, 1H), 7.48-7.59 (m, 4H), 7.93 (dd,J=1.2 Hz, 8.0 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H),8.25 (s, 1H), 8.31 (d, J=7.2 Hz, 2H), 8.51 (d, J=8.4 Hz, 1H); MS (ES+):m/z 422 [MH⁺]; HPLC: t_(R)=2.02 min (OpenLynx, polar_(—)5 min).

cis-3-[8-Chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl4-nitrobenzoate

To a solution of{3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol(46.52 g, 105.5 mmol) and 4-nitrobenzoyl chloride (23.55 g, 126.9 mmol)in methylene chloride (260 mL) was added N,N-diisopropylethyl amine(55.17 mL, 316.7 mmol). The mixture was stirred at rt for 15 h. Yellowprecipitates were collected by filtration, washed with ethyl acetate,and dried to afford the title compound; ¹H NMR (CDCl₃, 400 MHz) δ2.70-2.78 (m, 4H), 2.96-3.02 (m, 1H), 3.81-3.86 (m, 1H), 4.41 (d, J=4.8Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 7.44-7.48 (m, 1H), 7.51-7.55 (m, 2H),7.58 (d, J=5.2 Hz, 1H), 7.88-7.96 (m, 5H), 8.16-8.19 (m, 214), 8.26-8.29(m, 2H), 8.33 (d, J=8.8 Hz, 1H), 8.54 (s, 1H); MS (ES+): m/z 590 [MH⁺];HPLC: t_(R)=4.37 min (OpenLynx, polar_(—)5 min).

{3-[8-Chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol

To a solution of7-[8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline(338 mg, 0.8 mmol) in dry THF (5 mL) was added 9-BBN (2.4 mL, 1.2 mmol,0.5M in THF) dropwise at 0° C. under nitrogen atmosphere. Thetemperature was slowly warmed to it overnight. The mixture was cooled to0° C., and 3 mL 1N aq. NaOH and 0.6 mL 30% aq. H₂O₂ were added, theresulting mixture was stirred at 0° C. for 10 min, then it for 30 min.The mixture was diluted with methylene chloride (30 mL), washed withbrine (2×20 mL), and dried over anhydrous sodium sulfate. The filtratewas concentrated under reduced pressure, and the crude material waspurified by silica gel column chromatography (eluting withhexanes:EtOAc=50:50→100% ethyl acetate), to obtain the title compound asa yellow solid, a mixture of cis and trans isomers in the ratio of 5:1;MS (ES+): m/z 441/443 (3/1) [MH⁺]; ¹H NMR (CDCl₃, 400 MHz) δ 2.44-2.64(m, 6H), 3.65-3.76 (m, 3H), 7.31, 7.33 (2×d, J=5.0 Hz, 1H, 1:5 ratio),7.39-7.57 (m, 4H), 7.86-7.98 (m, 3H), 8.18 (m, 2H), 8.26 (d, J=8.6 Hz,1H), 8.51, 8.53 (2×s, 1H, 5:1 ratio).

7-[8-Chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline

N-[(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl]-3methylenecyclobutanecarboxamide (0.02 mmol, 10 g) was dissolved in 150mL POCl₃ in a 250 mL rbf, charged with 0.1 mL DMF and heated to 55° C.under a consistent N₂ flow for 1 h (the reaction was vented with aneedle). The excess POCl₃ was removed under reduced pressure and theresidue was quenched with 2 N NH₃ in isopropanol (250 mL) at 0° C. andwater. The aqueous layer was washed with DCM (100 mL×2) and the combinedorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography (flash column) eluting with 20-50% EtOAc inhexane. Concentration in vacuo of the product-rich fractions affordedthe desired product as yellow solid; MS (ES, Pos.): m/z 423 (100) [MH⁺];¹H NMR (CDCl₃, 400 MHz) δ 3.28-3.31 (m, 2H), 3.39-3.42 (m, 2H),3.85-3.93 (m, 1H), 4.94 (p, J=2.4 Hz, 2H), 7.38 (d, J=4.9 Hz, 1H),7.42-7.57 (m, 4H), 7.89-7.92 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (dd, J=8.6Hz, 0.8 Hz, 1H), 8.53 (s, 1H).

3-Methylenecyclobutanecarboxylic acid[(3-chloropyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-amide

C-(3-Chloro-pyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (690 mg,1.99 mmol) was dissolved in 6.0 mL of CH₂Cl₂ followed by the addition ofEDC (600 mg, 2.98 mmol) and HOBT (300 mg, 1.99 mmol).3-Methylenecyclobutanecarboxylic acid (300 mg, 2.59 mmol) was dissolvedin 1.0 mL of CH₂Cl₂ and added to the homogenous reaction mixture. After24 h the reaction was concentrated in vacuo and dissolved in EtOAc andthe organic layer was washed with sat. NaHCO₃. The organic layer waswashed with H₂O and brine. The organic layers where combined, dried oversodium sulfate, filtered and concentrated in vacuo. The crude productwas purified by silica gel column chromatography [Jones Flashmaster, 10g cartridge, eluting with 50% EtOAc: Hex] to obtain the desired productas a white fluffy solid; ¹H NMR (400 MHz, CDCl₃): δ=2.82-2.92 (m, 2H),2.99-3.06 (m, 2H), 4.77-4.80 (m, 2H), 6.81 (d, 1H, J=7.8 Hz), 7.45-7.54(m, 3H), 7.83-7.88 (m, 3H), 8.10 (d, 2H, J=7.1 Hz), 8.22-8.23 (brm, 1H),8.39 (d, 1H, J=1.79 Hz), 8.59 (d, 1H, J=2.5 Hz); MS (ES+): 440.93 (M+1),442.91 (M+3).

Method X7: General procedure for the synthesis of compounds of FormulaI-C′″.3 (compound of Formula I-C′″ where Q¹=2-phenyl-quinolin-7-yl andZ=cis-1,3-cyclobutyl) from compounds of Formula I-H.2 (Compound ofFormula I-H where Q¹=2-phenyl-quinolin-7-yl and Z=cis-1,3-cyclobutyl): Asealed tube containing a solution of cis-toluene-4-sulfonic acid3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester (85 mg, 0.15 mmol) in THF (3 mL) was charged with HNR²R³ (3.6mmol), sealed, and heated at 50° C. overnight. The mixture wasconcentrated and the residue was purified by mass-directed purificationto afford the desired product.

Example Structure Name HNR²R³ MS 1HNMR 58

cis-3-(3-Azetidin-1- ylmethyl-cyclobutyl)- 1-(2-phenyl-quinolin-7-yl)-imidazo[1,5- a]pyrazin-8-ylamine

m/z 461 [MH⁺]. (CDCl₃, 400 MHz): δ = 2.01- 2.11 (m, 2H), 2.31-2.36 (m,2H), 2.49-2.74 (m, 5H), 3.23- 3.25 (m, 4H), 3.68 (m, 1H), 5.18 (br s,2H, NH₂), 7.10 (m, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.46-7.57 (m, 3H),7.91-7.95 (m, 3H), 8.19-8.21 (m, 2H), 8.27 (d, J = 8.5 Hz, 1H), 8.43 (s,1H). 59

cis-3-{3- [(Dimethylamino) methyl]cyclobutyl}- 1-(2-phenyl quinolin-7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 449.34 (100) [MH⁺]. HPLC: t_(R) = 1.75 min (OpenLynx, polar_5 min)60

cis-N-[2-({[3-(8- Amino-1-(2- phenylquinolin-7- yl)imidazo[1,5-a]pyrazin-3- yl)cyclobutyl]methyl} amino)ethyl] acetamide

m/z 506.39 (100) [MH⁺]. HPLC: t_(R) = 1.73 min (OpenLynx, polar_5 min)61

cis-1-{[3-(8-Amino- 1-(2-phenylquinolin- 7-yl)imidazo[1,5- a]pyrazin-3-yl)cyclobutyl]methyl} piperidine-4- carboxamide

m/z 532.40 (100) [MH⁺]. HPLC: t_(R) = 1.72 min (OpenLynx, polar_5 min)62

cis- 3-[3-(Morpholin- 4- ylmethyl)cyclobutyl]- 1-(2-phenylquinolin-7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 491.33 (100) [MH⁺]. HPLC: t_(R) = 1.75 min (OpenLynx, polar_5 min)63

cis-3-{3- [(Diethylamino) methyl]cyclobutyl}- 1-(2- phenylquinolin-7-yl)imidazo[1,5- a]pyrazin-8-ylamine

MS (ES+): m/z 417.12 (100) [MH⁺]. HPLC: t_(R) = 1.86 min (OpenLynx,polar_5 min) 64

cis-3-[3-(Pyrrolidin-1- ylmethyl)cyclobutyl]- 1-(2-phenylquinolin-7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 475.17 (100) [MH⁺]. HPLC: t_(R) = 1.73 min (OpenLynx, polar_5 min)65

cis-3-{3-[(4- Methylpiperazin-1- yl)methyl]cyclobutyl}-1-(2-phenylquinolin- 7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 504.18 (100) [MH⁺]. HPLC: t_(R) = 1.65 min (OpenLynx, polar_5 min)

The compounds of Formula I-C′″.4 (compound of Formula I-C′″ zhereQ¹=2-phenyl-quinolin-7-yl and Z=trans-1,3-cyclobutyl) were prepared fromcompounds of Formula I-H.3 (Compound of Formula I-H whereQ¹=2-phenyl-quinolin-7-yl and Z=trans-1,3-cyclobutyl: according toMethod X7 except trans-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester was used in place of cis-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester:

Example Structure Name HNR²R³ MS 1HNMR 66

trans-3-(3-Azetidin-1- ylmethyl-cyclobutyl)-1- (2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8- ylamine

m/z 461 [MH⁺]. (400 MHz, CDCl₃): δ = 8.43 (d, J = 1.2 Hz, 1H), 8.26 (dd,J = 0.4, 8.0 Hz, 1H), 8.21-8.18 (m, 2H), 7.95 (d, J = 0.8 Hz, 2H), 7.92(d, J = 8.0 Hz, 1H), 7.56-7.47 (m, 3H), 7.10 (s, 2H), 5.20 (b, 2H), 3.82(p, J = 2.0 Hz, 1H), 3.26 (t, J = 6.8 Hz, 4H), 2.76-2.73 (m, 2H), 2.67(d, J = 8.0 Hz, 2H), 2.68-2.65 (m, 1H), 2.31- 2.29 (m, 2H), 2.13 (p, J =7.2 Hz, 2H) 67

trans-3-{3- [(Dimethylamino)methyl] cyclobutyl}-1-(2-phenyl quinolin-7-yl)imidazo[1,5-a]pyrazin- 8-ylamine

m/z 449.37 (100) [MH⁺]. HPLC: t_(R) = 1.75 min (OpenLynx, polar_5 min)68

trans-3-[3-(Morpholin-4- ylmethyl)cyclobutyl]-1- (2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin- 8-ylamine

MS (ES+): m/z 491.37 (100) [MH⁺]. HPLC: t_(R) = 1.78 min (OpenLynx,polar_5 min)

trans- andcis-3-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylp-toluenesulfonate were prepared as follows: A solution of3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethylcyclobutanol(500 mg, 1.14 mmol), 4 A molecular sieve (30 mg) and pyridine (0.92 mL,11.4 mmole) in dry methylene chloride (10 mL) was added a solution ofTs₂O (558 mg, 1.71 mmol) in methylene chloride (2 mL) at −40° C. underN₂ atmosphere through a syringe. The mixture was slowly warmed to rtovernight. The reaction was quenched with water (10 mL), diluted withmethylene chloride (30 mL), washed with sat. aq. NaHCO₃ (3×30 mL), anddried over Na₂SO₄, concentrated under reduced pressure, and purified bysilica gel column chromatography (eluting withHexanes:EtOAc=50:50→30:70→100% ethyl acetate, then 2% MeOH/EtOAc) toafford the individual cis and trans-desired products:

Example 69cis-3-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylp-toluenesulfonate

Yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 2.32 (s, 3H), 2.60-2.69 (m, 4H),3.85-3.93 (m, 1H), 4.26 (s, 2H), 7.05 (d, J=4.8 Hz, 1H), 7.11 (d, J=5.2Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.47-7.57 (m, 3H), 7.73 (d, J=8.4 Hz,211), 7.90-7.99 (m, 3H), 8.19-8.21 (m, 2H), 8.29 (d, J=8.4 Hz, 1H), 8.40(s, 1H); MS (ES+): m/z 592 [MH⁺]; HPLC: t_(R)=2.42 min (OpenLynx,polar_(—)5 min).

Example 70trans-3-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylp-toluenesulfonate

Yellow solid; ¹H NMR (CDCl₃, 400 MHz: S 2.46 (s, 3H), 2.56-2.61 (m, 2H),2.82-2.87 (m, 2H), 3.44-3.49 (m, 1H), 4.12 (s, 2H), 5.24 (br, NH),7.14-7.17 (m, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.48-7.56 (m, 3H), 7.84-7.95(m, 5H), 8.17-8.20 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.39 (s, 1H); MS(ES+): m/z 592 [MH⁺]; HPLC: t_(R)=2.53 min (OpenLynx, polar_(—)5 min).

Example 713-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol

Ammonia gas was bubbled in to IPA (5 mL, containing 2N NH₃) at −78° C.,until the volume was doubled (10 mL), and this solution was added to aslurry of3-[8-chloro-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethylcyclobutanolin IPA (2 mL, containing 2N NH₃) at −78° C. The reaction mixture washeated in a high pressure bomb at 120° C. for 36 h. The reaction mixturewas cooled to RT and evaporated to afford the desired product as ayellow solid; MS (ES+): m/z 438.02 [MH⁺]; HPLC: t_(R)=2.52 min(OpenLynx, polar_(—)5 min).

3-[8-Chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol

7-[8-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline(0.26 mmol, 110 mg) was dissolved in 8 mL solution (THF:H₂O=3: 1) andcharged with NMO (0.52 mmol, 0.18 mL, 50% aq. solution) and K₂Os₄.H₂O(0.26 mmol, 9.6 mg). The resulting mixture was stirred at rt overnight.The reaction was quenched with Na₂SO₃ (1.30 mmol, 164 mg), diluted withEtOAc (40 mL), washed with brine (30 mL), and dried over anhydroussodium sulfate. The filtrate was concentrated under reduced pressure togive the desired product as a yellow solid; MS (ES+): m/z 457/396 (10/1)[MH⁺].

The compounds of Formula I-N.1 (compound of Formula I-N whereQ¹=2-phenyl-quinolin-7-yl and Z=trans-1,3-cyclobutyl) were prepared fromcompounds of Formula I-M.1 (Compound of Formula I-M whereQ¹=2-phenyl-quinolin-7-y, A⁴=OTs, and Z=cis-1,3-cyclobutyl) according toMethod X7 exceptcis-3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylp-toluenesulfonate was used in place of trans-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester:

Exam- ple Structure Name HNR²R³ Analytical data 72

trans-3-[8-Amino-1-(2- phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(azetidin-1- ylmethyl)cyclobutanol

m/z 477 [MH⁺]. HPLC: t_(R) = 1.72 min (OpenLynx, polar_5 min); ¹H NMR(CDCl₃, 400 MHz) δ 2.08- 2.12 (m, 2H), 2.55-2.67 (m, 6H), 3.32 (t, J =6.8 Hz, 4H), 3.98-4.02 (m, 1H), 5.19 (br, 2H), 7.11-7.15 (m, 2H),7.47-7.57 (m, 3H), 7.92-7.96 (m, 3H), 8.18-8.21 (m, 2H), 8.28 (d, J =8.4 Hz, 1H), 8.44 (s, 1H). 73

trans-3-[8-Amino-1-(2- phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1- (dimethylamino-1- ylmethyl)cyclobutanol

m/z 465 [MH⁺]. HPLC: t_(R) = 1.72 min (OpenLynx, polar_5 min) 74

trans-3-[8-Amino-1-(2- phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(pyrrolidin-1- ylmethyl)cyclobutanol

m/z 491 [MH⁺]. HPLC: t_(R) = 1.76 min (OpenLynx, polar_5 min); ¹HNMR(CDCl₃, 400 MHz): δ = 1.75-1.79 (m, 4H), 2.58-2.63 (m, 4H), 2.66- 2.72(m, 6H), 4.00-4.05 (m, 1H), 5.19 (br, 2H), 7.11 (d, J = 5.2 Hz, 1H),7.17 (d, J = 4.8 Hz, 1H), 7.46-7.57 (m, 3H), 7.91-7.97 (m, 3H),8.18-8.20 (m, 2H), 8.27 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H). 75

trans-[2-({[3-(8-Amino-1-(2- phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-1- ydroxycyclobutyl]methyl}amino) ethyl]acetamide

m/z 465 [MH⁺]. HPLC: t_(R) = 1.72 min (OpenLynx, polar_5 min).

The compounds of Formula I-N.2 (compound of Formula I-N whereQ¹=2-phenyl-quinolin-7-yl and Z=cis-1,3-cyclobutyl) were prepared fromcompounds of Formula I-M.2 (Compound of Formula I-M whereQ¹=2-phenyl-quinolin-7-y, A⁴═OTs, and Z=trans-1,3-cyclobutyl) accordingto Method X7 excepttrans-3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-hydroxycyclobutylmethylp-toluenesulfonate was used in place of cis-toluene-4-sulfonic acid3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethylester:

Example Structure Name HNR²R³ Analytical data 76

cis-3-[8-Amino-1-(2- phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(azetidin-1- ylmethyl)cyclobutanol

m/z 477 [MH⁺]; HPLC: t_(R) = 1.77 min (OpenLynx, polar_5 min); 1HNMR(CDCl₃, 400 MHz) δ 2.12-2.19 (m, 2H), 2.61-2.73 (m, 4H), 2.73 (s, 2H),3.35-3.43 (m, 5H), 5.23 (br, 2H), 7.12 (d, 5.2 Hz, 1H), 7.20 (d, J = 4.8Hz, 1H), 7.46-7.56 (m, 3H), 7.91-7.95 (m, 3H), 8.18-8.20 (m, 2H), 8.27(dd, J = 0.8 Hz, J = 8.8 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H) 77

cis-3-[8-Amino-1-(2- phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(pyrrolidin-1- ylmethyl)cyclobutanol

m/z 491 [MH⁺]; HPLC: t_(R) = 1.76 min (OpenLynx, polar_5 min); 1HNMR(CDCl₃, 400 MHz): δ = 1.79-1.83 (m, 4H), 2.66-2.71 (m, 6H), 2.80-2.85(m, 4H), 3.35-3.39 (m, 1H), 5.22 (br, 2H), 7.12 (d, J = 4.8 Hz, 1H),7.22 (d, J = 5.2 Hz, 1H), 7.48-7.56 (m, 3H), 7.92 (d, J = 8.8 Hz, 1H),7.95 (d, J = 1.2 Hz, 2H), 8.18-8.20 (m, 2H), 8.27 (dd, J = 0.4 Hz, J =8.4 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H)

Method X5: General procedure for the synthesis of compounds of FormulaI-C′″.1 (compound of Formula I-C′″ where Q¹=2-phenyl-quinolin-7-yl andR²═H) from compounds of Formula I-C″.1 (Compound of Formula I-C″ whereQ¹=2-phenyl-quinolin-7-yl):

trans-3-(4-Aminomethylcyclohexyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine(1.00 g; 2.23 mmol) was dissolved in CH₂Cl₂ (17 mL) and charged withPS-DIEA (1.20 g, 3.72 mmol/g loading, 4.46 mmol). Under N₂ atmosphere,Reagent C (1.11 mmol) was then added in one portion. After 15 min, thereaction was monitored by TLC, and additional Reagent C (0.56 mmol) wasadded. Over the next 30 min., additional Reagent C was added in twodifferent portions (0.27 mmol and 0.11 mmol). When the reaction wasalmost complete by LC/MS, the reaction was filtered, and the resins wererinsed multiple times with CH₂Cl₂, chloroform, 10% CH₃OH/CH₂Cl₂. Thefiltrate was concentrated and the bright orange/yellow solid wasdissolved in CH₂Cl₂, then loaded onto Hydromatrix. The crude product waspurified by purified by silica gel column chromatography [JonesFlashmaster, 20 g/75 mL cartridge, 100% CH₂Cl₂, to 2% 7N ammonia inCH₃OH/CH₂Cl₂] to afford the desired product of >90% purity by LC/MS. Theproduct was further purified by recrystallization from THF/diethyl etherto obtain the desired product as a yellow solid. When Reagent C was acarboxylic acid, the following procedure was used:trans-3-(4-Aminomethylcyclohexyl)-1-(2-phenylquinolin-7yl)imidazo[1,5-a]pyrazin-8-ylamine(100 mg, 0.223 mmol) was dissolved in CH₂Cl₂ (1 mL) and was charged withReagent C (0.22 mmol), EDC (64 mg, 0.33 mmol), and PS-DIEA (120 mg, 0.45mmol, 3.9 mmol/g loading). When the reaction progress was monitored withLC/MS after 15 min., the reaction consisted of the starting amine,mono-acylated, and di-acylated products (16%, 74%, and 10%respectively). The reaction was filtered, and the resins were rinsedmultiple times with CH₂Cl₂, chloroform, 10% CH₃OH/CH₂Cl₂. The brightorange/yellow solid was dissolved in methanol and purified by MDP toobtain the desired product as a yellow powder.

Compounds of Formula I-C′″.1 (compound of Formula I-C′″ whereQ¹=2-phenyl-quinolin-7-yl and R²═H) were prepared from compounds ofFormula I-C″.1 (Compound of Formula I-C″ whereQ¹=2-phenyl-quinolin-7-yl) by Method X5:

Example Structure Name Reagent C Analytical data 78

N-({trans-4-[8-Amino(2- phenylquinolin-7- yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}- methyl)acetamide Ac₂O m/z 491.31 (15) [MH⁺], 246.44(100) [MH-244]; ¹HNMR (CD₃OD, 400 MHz) δ 8.48 (d, J = 8.8 Hz, 1H), 8.33(dd, J = 0.8. 0.8 Hz, 1H), 8.18 (m, 2H), 8.10 (d, J = 8.8 Hz, 1H), 8.07(d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.4, 1.6 Hz, 1H), 7.62 (d, J = 5.2Hz, 1H), 7.60-7.48 (m, 3H), 7.06 (d, J = 5.2 Hz, 1H), 3.16 (m, 1H), 3.12(d, J = 6.8 Hz, 2H), 2.11 (m, 2H), 1.83 (ddd, J = 25.2, 12.8, 2.4 Hz,1H), 1.65 (m, 1H), 1.26 (ddd, J = 25.2, 12.8, 2.4 Hz, 1H). 79

N-({trans-4-[8-Amino(2- phenylquinolin-7- yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methyl)- N′-ethylurea EtNCO m/z 520.42 (100) [MH⁺],521.41 (55)[M⁺²], 522.39 (15) [M⁺³] 80

N-({trans-4-[8-Amino(2- phenylquinolin-7- yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methyl)- 2-methoxyacetamide

m/z 522.13 (40) [MH⁺], 523.14 (20)[M⁺²], 524.16 (10) [M⁺³], 261.87 (100)[M-259]. 81

N-({trans-4-[8-amino(2- phenylquinolin-7- yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methyl)- tetrahydrofuran-3- carboxamide

m/z 547.10 (40) [MH⁺], 548.12 (70) [MH⁺²], 549.13 (35) [MH⁺³], 550.12(10) [MH⁺⁴], 450.13 (30) [M-97], 274.70 (100) [MH-272]; ¹HNMR (CDCl₃,400 MHz) δ 8.41 (ddd, J = 0.8, 0.8 Hz, 1H), 8.39 (s, 1H), 8.29 (d, J =8.8 Hz, 1H), 8.20 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.4,1.6 Hz, 1H), 7.55 (m, 2H), 7.49 (m, 1H), 7.24 (d, J = 5.6 Hz, 1H), 6.94(d, J = 5.2 Hz, 1H), 5.74 (t, J = 2.8 Hz, 1H), 3.97 (ddd, J = 8.8, 7.2,7.2 Hz, 1H), 3.93 (quin, J = 7.2 Hz, 2H), 3.83 (ddd, J = 8.4, 7.2, 7.2Hz, 1H), 3.22 (t, J = 6.6 Hz, 2H), 2.92 (m, 2H), 2.30-2.10 (m, 4H),2.00-1.50 (m, 4H), 1.64 (m, 1H), 1.22 (m, 2H). 82

N-({trans-4-[8-Amino(2- phenylquinolin-7- yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methyl)- tetrahydrofuran-2- carboxamide

m/z 547.17 (65) [MH⁺], 548.17 (60) [MH⁺²], 549.13 (20) [MH⁺³], 550.14(5) [MH⁺⁴], 449.13 (35) [M-98], 274.48 (100) [MH-272]

Method X6: General procedure for the synthesis of compounds of FormulaI-C′″.2 (compound of Formula I-C′″ where Q¹=2-phenyl-quinolin-7-yl) fromcompounds of Formula I-H.1 (Compound of Formula I-H whereQ¹=2-phenyl-quinolin-7-yl):

To an anhydrous THF solution (1.5 mL) of trans-toluene-4-sulfonic acid4-[8-amino-1-(3-benzyloxy-phenyl)imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethylester (100 mg, 0.17 mmol) in a sealed tube, HNR²R³ (8.28 mmol) was addedand stirred at 60° C. for 72 h. The reaction mixture was concentrated invacuo and partitioned between EtOAc and sat. NaHCO₃. The organic layerwas washed with sat. NaHCO₃ (2×), water, brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to a yellow oil. The crude materialwas purified by MDPS to yield the desired product as a light yellowpowder.

The compounds of Formula I-C′″.2 (compound of Formula I-C′″ whereQ¹=2-phenyl-quinolin-7-yl) were prepared from compounds of Formula I-H.1(Compound of Formula I-H where Q¹=2-phenyl-quinolin-7-yl) according toMethod X6:

Example Structure Name HNR²R³ Analytical Data 83

(trans-3-[4- (Dimethylamino)- methyl-cyclohexyl]- 1-(2-phenylquinolin-7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 477.19 (25) [MH⁺], 478.20 (10) [MH⁺²], 239.51 (100) [MH-237]; ¹HNMR(CDCl₃, 400 MHz) δ 8.41 (dd, J = 0.8, 0.8 Hz, 1H), 8.27 (dd, J = 8.8,0.4 Hz, 1H), 8.19 (m, 2H), 7.97- 7.85 (m, 3H), 7.54 (m, 2H), 7.48 (m,1H), 7.29 (d, J = 5.2 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 5.19 (br s,2H), 2.97 (tt, J = 12.2, 3.4 Hz, 1H), 2.40-2.10 (m, 9H), 2.15 (m, 2H),1.95 (ddd, J = 27.2, 12.4, 3.2 Hz, 2H), 1.16 (m, 2H). 84

(trans-3-{4- [ethyl(methyl)amino] methyl-cyclohexyl}-1-(2-phenylquinolin- 7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 491.16 (30) [MH⁺], 492.17 (15) [MH⁺²], 246.52 (100) [MH-244]. 85

{trans-3-[4- (Pyrrolidinylamino)- methyl-cyclohexyl}-1-(2-phenylquinolin- 7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 503.18 (20) [MH⁺], 504.19 (10) [MH⁺²], 252.52 (100) [MH-250] 86

{trans-3-[4- (Morpholinylamino)- methyl-cyclohexyl}-1-(2-phenylquinolin- 7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 519.16 (20) [MH⁺], 520.17 (10) [MH⁺²], 260.47 (100) [MH-258] 87

{trans-3-[4- (Azetidinylamino)- methyl-cyclohexyl}- 1-(2-phenylquinolin-7-yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 489.13 (30) [MH⁺], 490.14 (10) [MH⁺²], 245.50 (100) [MH-243] 88

{trans-3-[4-(4- Methylpiperidinyl- amino)methyl- cyclohexyl}-1-(2-phenylquinolin-7- yl)imidazo[1,5- a]pyrazin-8-ylamine

m/z 532.19 (20) [MH⁺], 533.20 (10) [MH⁺²], 267.00 (100) [MH-245] 89

N-({trans-4-[8- Amino(2- phenylquinolin-7- yl)imidazo[1,5- a]pyrazin-3-yl]cyclohexyl}- methyl)piperidine-4- carboxamide

m/z 560.20 (10) [MH⁺], 561.21 (5) [MH⁺²], 280.90 (100) [MH-279]

Example 90(trans-3-[4-(Dimethylamino)methyl-cyclohexyl]-1-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine

Prepared according to Method X6 where HNR²R³ is dimethylamine;

¹H NMR (d₆-DMSO, 400 MHz) δ 8.35-8.25 (m, 2H), 8.23 (d, J=1.6 Hz, 1H),8.20 (d, J=8.4 Hz, 1H), 8.06 (s, 1H), 7.91 (dd, J=8.6, 1.8 Hz, 1H), 7.68(d, J=5.2 Hz, 1H), 7.60-7.45 (m, 3H), 7.09 (d, J=5.2 Hz, 1H), 6.19 (brs, 2H), 3.13 (tt, J=11.8, 3.2, 1H), 2.81 (s, 3H), 2.13 (s, 6H), 2.07 (d,J=7.2 Hz, 2H), 2.01 (m, 2H), 1.90 (m, 2H), 1.71 (ddd, J=25.4, 12.6, 2.4Hz, 2H), 1.56 (m, 1H), 1.10 (m, 2H); m/z 491.02 (5) [MH⁺], 246.29 (100)[MH-244]; t_(R)(polar-5 min/openlynx)=1.85 min.

Example 91(trans-3-{4-[Ethyl(methyl)amino]methyl-cyclohexyl}-1-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine

Prepared according to Method X6 where HNR²R³ is methylethylamine; ¹H NMR(d₆-DMSO, 400 MHz) δ 8.30 (d, J=7.6 Hz, 2H), 8.23 (s, 1H), 8.20 (d,J=8.4 Hz, 1H), 8.06 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.68 (d, J=4.8 Hz,1H), 7.56 (dd, J=7.2, 7.2 Hz, 2H), 7.50 (dd, J=7.0 Hz, 1H), 7.09 (d,J=5.2 Hz, 1H), 6.18 (br s, 2H), 3.12 (m, 1H), 2.81 (s, 3H), 2.34 (m,2H), 2.20-2.05 (m, 5H), 2.01 (d, J=12.0 Hz, 2H), 1.91 (d, J=11.6 Hz,2H), 1.70 (dd, J=24.0, 11.6 Hz, 2H), 1.58 (m, 1H), 1.29 (m, 2H), 1.10(m, 2H), 0.98 (t, J=7.0 Hz, 3H); m/z 505.06 (10) [MH⁺], 253.36 (100)[MH-251]; t_(R)(polar-5 min/openlynx)=1.88 min.

Example 92{trans-3-[4-(Pyrrolidinylamino)methyl-cyclohexyl}-1-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine

Prepared according to Method X6 where HNR²R³ is pyrrolidine;

¹HNMR (d₆-DMSO, 400 MHz) δ 8.35-8.26 (m, 2H), 8.23 (d, J=1.2 Hz, 1H),9.20 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.91 (dd, J=8.6, 1.8 Hz, 1H), 7.68(d, J=4.8 Hz, 1H), 7.56 (dd, J=7.2, 7.2 Hz, 2H), 7.51 (dd, J=7.4, 7.4Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 6.19 (br s, 2H), 3.13 (m, 1H), 2.80 (s,3H), 2.41 (m, 4H), 2.27 (d, J=7.2 Hz, 21-1), 2.01 (m, 2H), 1.93 (m, 2H),1.80-1.62 (m, 6H), 1.55 (m, 1H), 1.12 (m, 2H); m/z 517.01 (10) [MH⁺],259.33 (100) [MH-257]; t_(R)(polar-5 min/openlynx)=1.89 min.

Example 93trans-{4-[8-Amino-1-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol/methyl4-methylbenzenesulfonate

trans-{4-[8-Amino-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol(200 mg, 0.43 mmol) and toluene-4-sulfonic anhydride (150 mg, 0.47 mmol)were dissolved in anhydrous pyridine (8.7 mL) under nitrogen and allowedto sit at −10° C. for 24 h. Saturated aqueous sodium bicarbonatesolution (10 mL) was added to the reaction mixture, then, stirred for 10min. The reaction mixture was concentrated in vacuo, then, partitionedbetween saturated aqueous sodium bicarbonate solution anddichloromethane. The organic extract was separated, washed once againwith sodium bicarbonate (aq) and brine, dried over anhydrous sodiumsulfate, then concentrated in vacuo. The crude mixture was purified by asilica gel column chromatography [Jones Flashmaster; 10 g column,dry-loaded with silica gel; eluted with 100% DCM to 1:1 EtOAc/DCM to 10%(7N ammonia/MeOH)/chloroform] to obtain the desired mono-tosylatedproduct as a yellow solid; ¹H NMR (d₆-DMSO, 400 Hz) δ 8.29 (dd, J=8.4,1.2 Hz, 2H), 8.22 (d, J=1.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (s,1H), 7.90 (dd, J=8.4, 1.2 Hz, 1H), 7.82 (m, 2H), 7.69 (d, J=5.2 Hz, 1H),7.563 (m, 2H), 7.50 (m, 3H), 7.08 (d, J=4.8 Hz, 1H), 6.19 (br s, 2H),3.92 (d, J=5.6 Hz, 2H), 3.10 (m, 1H), 2.08 (s, 3H), 2.44 (s, 3H), 2.00(m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.20 (m, 2H); MS (ES+): m/z 618.32(40) [MH⁺], 426.21 (60) [M-191], 412.52 (100) [M-205]; t_(R)(polar-5min/MDPS) 3.03 min.

Example 94trans-{4-[8-Amino-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol

A mixture of[4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (500mg, 1.34 mmol),4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline(510.2 mg, 1.48 mmol), and cesium carbonate (875 mg, 2.69 mmol) weredissolved in a 1:1 mixture of 1,2-dimethoxyethane and water (10 mL). Thereaction was degassed with nitrogen, then charged withtetrakis(triphenylphosphine)palladium(0) (155 mg, 0.13 mmol). Thereaction was degassed once again, then the mixture was heated at 75° C.for 18 h. The mixture was cooled to rt, was diluted with dichloromethaneand washed with brine. The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo. The yellow residue waspurified by a silica gel chromatography [Jones Flashmaster; 20 g column;eluted with 100% chloroform to 4% MeOH/chloroform to 4% (7Nammonia/MeOH)/chloroform] to give the desired product as a yellow solid.The product was contaminated with PPh₃ (0.053 equiv by ¹H NMR) andpinacol (0.549 equiv by ¹H NMR). The product was further purified by anacid-base aqueous work-up. The yellow solid was taken up indichloromethane (30 mL), then, the desired product was taken up in anaqueous layer with 1N aqueous HCl (30 mL). The acidic aqueous layer waswashed with dichloromethane, then basified with solid sodium bicarbonateuntil ˜pH 9 to 10. The basic aqueous layer was extracted withdichloromethane, then twice with chloroform. The organic extracts werecombined, dried over sodium sulfate, filtered, concentrated in vacuo anddried in an oven for 18 h to give the desired product as a yellow solid;¹H NMR (d₆-DMSO, 400 Hz) δ 8.30 (m, 2H), 8.23 (d, J=1.6 Hz, 1H), 8.20(d, J=8.8 Hz, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.8, 2.0 Hz, 1H), 7.70 (d,J=5.2 Hz, 1H), 7.57 (m, 2H), 7.51 (m, 1H), 7.09 (d, J=5.6 Hz, 1H), 6.19(br s, 2H), 3.31 (s, 3H), 3.12 (m, 1H), 2.81 (s, 3H), 2.03 (m, 2H), 1.88(m, 2H), 1.67 (m, 2H), 1.49 (m, 1H), 1.16 (m, 2H); MS (ES+): m/z 464.03(30) [MH⁺], 465.02 (10) [MH⁺2], 232.90 (100) [M-231]; t_(R)(polar-5min/openlynx) 2.20 min.trans-[4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol

trans-[4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol(26.50 g, 67.66 mmol) was charged in a 400 mL steel bomb and wasdissolved in 2M NH₃ in isopropanol (300 mL) and anhydrous THF (10 mL).The reaction mixture was cooled to −78° C. Ammonia gas was bubbledvigorously into the solution for 8 min; then the bomb was tightly sealedand heated to 120° C. for 20 h. The crude reaction mixture wasconcentrated in vacuo, then the reaction residue was taken up withMeOH/CHCl₃, loaded onto silica gel. The mixture was purified by a silicagel glass column chromatography [eluted with 1:1 CH₂Cl₂/EtOAc to 10%˜7 NNH₃ in MeOH/CHCl₃] to afford the desired product as a beige cream whitesolid; MS (ES+): m/z 373.01 (100) [MH⁺], 373.98 (50) [MH⁺2];t_(R)(polar-5 min/openlynx) 1.57 min.

trans-[4-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol

trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (18.00g, 67.74 mmol) and N-iodosuccinimide (19.81 g, 88.06 mmol) in anhydrousDMF (360 mL) were stirred at 60° C. under N₂ for 6 h. The reaction wasdiluted with DCM (˜600 mL), washed with water and brine, dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The crude material waspurified by a silica gel flash chromatography (eluted with 1:2 EtOAc/DCMto 1:1 EtOAc/DCM) to obtain the desired product as a pale yellow solid;By ¹H NMR analysis, the product was contaminated with 0.35 equiv ofNIS-impurity. The product was carried onto the next reaction withoutfurther purification; MS (ES+): m/z 391.92 (100) [MH⁺], 393.88 (50)[MH⁺2], 394.89 (10) [MH+3]; t_(R)(polar-5 min/openlynx) 2.79 min.

trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol

A THF solution (1.00 L) of trans-methyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (29.70 g,101.1 mmol) was cooled to −78° C. and was charged with LAH (1M in THF,25.3 mmol, 25.3 mL) dropwise. After 30 min., the reaction mixture wascharged with additional LAH (25.3 mmol) at −78° C. and then, allowed tostir at −78° C. for 1.5 h. The reaction was slowly warmed up to r.t. andstirred for additional 30 min. Ethyl acetate, Na₂SO₄.10H₂O, and silicagel were added to the reaction mixture and concentrated in vacuo to givean orange solid. The crude mixture was purified by a silica gel glasscolumn chromatography (eluted with 2:3 EtOAc/DCM to 100% EtOAc) toobtain the title compound as a slightly yellow-tinted white solid; ¹HNMR (CDCl₃, 400 MHz) δ 1.14-1.30 (m, 2H), 1.61-1.75 (m_(c), 1H), 1.84(ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.98-2.13 (m, 4H), 2.19 (s, br,—OH), 2.94 (tt, J=11.6, 3.2 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 7.31 (d,J=5.2 Hz, 1H), 7.64 (dd, J=5.2, 1.2 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H); MS(ES+): m/z 266.21/268.17 (100/89) [MH⁺]. HPLC: t_(R)=2.38 min (OpenLynx,polar_(—)5 min). MS (ES+): m/z 266.21 (100) [MH⁺], 268.17 (80) [MH⁺2},289.18 (20) [MH⁺3]; t_(R)(polar-5 min/openlynx) 2.36 min.

trans-Methyl4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate

trans-Methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexanecarboxylate(29.00 g, 93.02 mmol) was dissolved in anhydrous acetonitrile (930 mL)and anhydrous DMF (9 mL) and heated at 55° C. under nitrogen for 3 h.The reaction mixture was concentrated in vacuo, then, the solid residuewas taken up in DCM, then, basified to pH 10 with 2M ammonia inisopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM,then, loaded onto TEA-basified silica gel. The crude product waspurified by a silica gel column chromatography (eluted with 2:3EtOAc/DCM) to obtain the title compound as a yellow powder; ¹H NMR(CDCl₃, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85(ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H),2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt,J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61(d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86)[MH⁺]. HPLC: t_(R)=2.85 min (OpenLynx, polar_(—)5 min).

trans-Methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate

A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid(15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under anitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixturewas cooled to r.t., then, (3-chloropyrazin-2-yl)methylaminebis-hydrochloride salt (16.00 g, 73.91 mmol) and DIPEA (31.52 g, 244.00mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, thereaction was concentrated in vacuo. The crude reaction mixture waspurified by a silica gel glass column chromatography (eluted with 3:2DCM/EtOAc) to obtain the pure desired product as a slightly yellowishcreamy white powder; ¹H NMR (CDCl₃, 400 MHz) δ 1.43-1.65 (m, 4H),2.01-2.14 (m, 4H), 2.25 (tt, J=12.0, 3.6 Hz, 1H), 2.34 (tt, J=11.6, 3.2Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, —NH),8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12(84/32) [MH⁺]; HPLC: t_(R)=2.44 min (OpenLynx, polar_(—)5 min).

Example 957-(trans-3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

A solution of toluene-4-sulfonic acidtrans-3-[4-amino-5-(2-phenylquinolin-7-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester and azetidine (0.30 mL, 254 mg, 4.5 mmol) in THF (4 mL) was heatedin a sealed tube to 50° C. overnight. More azetidine (0.30 mL, 254 mg,4.5 mmol) was added, and heating was continued overnight. THF wasevaporated, water and saturated NaHCO₃ solution. were added, the mixturewas extracted with CH₂Cl₂ (5×20 mL), and the combined CH₂Cl₂ extractswere washed with water and brine and dried over MgSO₄. The crudematerial was purified by chromatography on silica gel [JonesFlashmaster, 5 g/25 mL cartridge, eluting with CH₂Cl₂ (1-9)→5% MeOH inCH₂Cl₂ (10-31)→6.6% MeOH in CH₂Cl₂ (32-55)→6.6% MeOH in CH₂Cl₂+NH₃ (0.05M) (56-86)], yielding the title compound as a highly viscous yellow oil.This oil was dissolved in CDCl₃ (0.7 mL), tBuOMe was added, and theoff-white precipitate was filtered off and dried in vacuo yielding thedesired product. ¹H NMR (CDCl₃, 400 MHz) δ 2.15 (quint, J=7.2 Hz, 2H),2.33-2.54 (m, 4H), 2.57-2.70 (m, 3H), 2.73 (d, J=7.4 Hz, 2H), 3.33 (t,J=7.2 Hz, 4H), 5.26 (brs, 2H), 5.44 (quint, J=8.1 Hz, 1H), 7.37 (s, 1H),7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.7, 8.3 Hz, 1H), 7.91(d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d,J=8.6 Hz, 1H), 8.28-8.31 (m, 1H), 8.35 (s, 1H). ¹³C NMR (CDCl₃, 100.6MHz, DEPT135) δ 17.73 (−), 27.06 (+), 33.60 (2C, −), 46.72 (+), 55.51(2C, −), 63.99 (−), 101.05 (C_(quart)), 116.12 (C_(quart)), 118.85 (+),120.57 (+), 125.86 (C_(quart)), 127.29 (+), 127.45 (2C, +), 128.18 (+),128.34 (+), 128.76 (2C, +), 129.41 (+), 136.31 (C_(quart)), 136.46 (+),139.30 (C_(quart)), 148.38 (C_(quart)), 150.73 (C_(quart)), 151.83 (+),157.07 (C_(quart)), 157.95 (C_(quart)). MS (ES+): m/z 461.2 (11) [MH⁺],338.2 (14) [MH⁺-C₄H₅CH₂azetidine]. HPLC: t_(R)=2.0 min (OpenLynx,polar_(—)5 min).

Example 96 Toluene-4-sulfonic acidtrans-3-[4-amino-5-(2-phenylquinolin-7-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester

To a suspension oftrans-{3-[4-amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol(105.7 mg, 0.251 mmol) in CH₂Cl₂ (5 mL) and pyridine (1 mL), cooled in adry ice/acetone bath, was added a solution of Ts₂O (92 mg, 0.28 mmol) inCH₂Cl₂ (2 mL) over 5 min, then the reaction mixture was warmed up toambient temperature and stirred for 16 h. More Ts₂O (70 mg, 0.21 mmol)was added, and stirring at ambient temperature was continued for 4.5 h.The reaction solution was diluted with CH₂Cl₂ (25 mL), water andsaturated NaHCO₃ sol. were added, the layers were separated, the aqueouslayer was extracted with CH₂Cl₂ (3×25 mL), and the combined CH₂Cl₂extracts were washed with water and brine and dried over MgSO₄.Filtration and concentration after adding toluene (10 mL; to removeremaining pyridine as azeotrop) gave the desired product. Nopurification before the next step. ¹H NMR (CDCl₃, 400 MHz) δ 2.43-2.51(m, 2H), 2.47 (s, 2H), 2.67-2.86 (m, 3H), 4.22 (d, J=6.6 Hz, 2H), 5.19(brs, 2H), 5.36 (quint, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.37-7.41 (m, 2H),7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.68 (dd, J=1.8, 8.4 Hz, 1H),7.83-7.87 (m, 2H), 7.92 (d, J=8.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H),8.17-8.22 (m, 2H), 8.25-8.29 (m, 2H), 8.33 (s, 1H). MS (ES+): m/z 576.1(54) [MH⁺], 338.2 (10) [MH⁺-cyclobutene-CH₂OTs]. HPLC: t_(R)=2.8 min(OpenLynx, nonpolar_(—)5 min).

General procedure for the Suzuki coupling with2-Phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline

Nitrogen is bubbled through a mixture of a5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (0.10 mmol),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (34mg, 0.10 mmol; 1 equiv.), Na₂CO₃ (26 mg, 0.25 mmol; 2.5 equiv.), andPd(PPh₃)₄ (7 mg, 0.006 mmol; 6 mol %) in DMF (2.5 mL)/water (0.5 mL) for2-5 min at ambient temperature, then the mixture is heated to 80° C.overnight under nitrogen, after which time the reaction is typicallycomplete. The solvents are evaporated, and water and CH₂Cl₂ are added.If necessary, the mixture is filtered through diatomaceous earth toremove a precipitate of palladium black. The layers are separated, theaqueous layer is extracted with CH₂Cl₂ (2×), and the combined organicextracts are washed with brine, dried over MgSO₄, filtered andconcentrated. If deemed necessary, a preliminary purification on an SCXcolumn effects removal of non-basic impurities. The crude material ispurified by chromatography on silica gel or HPLC.

Example 97trans-{3-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanol

Following the general procedure for the Suzuki coupling,trans-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-A-cyclobutyl]-methanol(139.2 mg, 0.4045 mmol) was reacted with2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (141mg, 0.426 mmol), Na₂CO₃ (107 mg, 1.01 mmol) and Pd(PPh₃)₄ (30 mg, 0.026mmol) in DMF (10 mL)/water (2 mL). The crude material was purified bycolumn chromatography on silica gel [Jones Flashmaster, 10 g/70 mLcartridge, eluting with CH₂Cl₂ (1-7)→2% MeOH in CH₂Cl₂ (8-22)→5% MeOH inCH₂Cl₂ (23-41)→7% MeOH in CH₂Cl₂ (42-51)], yielding the title compound.¹H NMR (CDCl₃, 400 MHz) δ 2.42-2.60 (m, 3H), 2.60-2.73 (m, 3H), 3.88 (d,J=6.4 Hz, 2H), 5.19 (brs, 214), 5.44-5.53 (m_(c), 1H), 7.39 (s, 1H),7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.7, 8.3 Hz, 1H), 7.92(d, J=8.5 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d,J=8.5 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). ¹³C NMR (CDCl₃, 100.6MHz, DEPT135) δ 30.62 (+), 32.16 (2C, −), 46.70 (+), 65.12 (−), 101.04(C_(quart)), 116.13 (C_(quart)), 118.88 (+), 120.64 (+), 125.82(C_(quart)), 127.27 (+), 127.45 (2C, +), 128.17 (+), 128.21 (+), 128.71(2C, +), 129.40 (+), 136.23 (C_(quart)), 136.49 (+), 139.23 (C_(quart)),148.28 (C_(quart)), 150.47 (C_(quart)), 151.57 (+), 157.09 (C_(quart)),157.97 (C_(quart)). MS (ES+): m/z 422.1 (51) [MH⁺], 338.2 (39)[MH⁺-cyclobutene-CH₂OH]. HPLC: t_(R)=2.4 min (OpenLynx, polar_(—)5 min).

trans-[3-(4-Amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl]methanol

Gaseous ammonia (from a lecture bottle) was condensed into a suspensionoftrans-[3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol(172.6 mg, 0.475 mmol) in dioxane (3 mL) and iPrOH (3 mL) in a sealableglass tube, cooled by dry ice/acetone, until the volume increased by ≈2mL, then the tube was sealed and heated to 90° C. overnight. Thesolvents were evaporated, water was added to the residue, and the paleyellow solid was filtered off and dried in vacuo to give the titlecompound as a pale yellow solid. The compound was used in the next stepwithout further purification. ¹H NMR (CDCl₃, 400 MHz) δ 2.41-2.52 (m,2H), 2.52-2.64 (m, 3H), 3.83 (d, J=6.3 Hz, 2H), 5.30-5.40 (m_(c), 1H),5.60 (brs, 2H), 7.29 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 345.1 (100)[MH⁺]. HPLC: t_(R)=1.9 min (OpenLynx, polar_(—)5 min).

trans-[3-(4-Chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol

To a solution oftrans-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid methyl ester (trans/cis=5:1) (116.5 mg, 0.297 mmol) in CH₂Cl₂ (5mL), cooled by dry ice/acetone, was added DIBAL (1M in toluene, 0.65 mL,0.65 mmol). After 40 min, the dry ice/acetone bath was replaced with andice/water bath. The reaction was quenched 2 h later by adding potassiumsodium tartrate solution, the mixture was extracted with CH₂Cl₂ (3×20mL), the combined extracts were washed with NaHCO₃ solution and brine,dried over MgSO₄, filtered, and concentrated to give the target compoundas 5:1 trans/cis mixture. This material was chromatographed on silicagel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH₂Cl₂(1-8)→CH₂Cl₂:EtOAc 9:1 (9-19)→CH₂Cl₂:EtOAc 5:1 (20-47)→CH₂Cl₂:EtOAc 3:1(48-60)] to give the title compound with trans/cis=25:1. A forerunningfraction enriched with the cis isomer was also isolated. NMR (CDCl₃, 400MHz) δ 2.42-2.57 (m, 2H), 2.58-2.72 (m, 3H), 3.85 (brs, 2H), 5.36-5.48(m_(c), 1H), 7.61 (s, 1H), 8.60 (s, 1H). MS (ES+): m/z 363.9/365.9(100/36) [MH⁺]. HPLC: t_(R)=3.0 min (OpenLynx, polar_(—)5 min).

trans-3-(4-Chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid methyl ester

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (preparedaccording to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7),1984-92) (280 mg, 1.00 mmol), cis-3-hydroxycyclobutanecarboxylic acidmethyl ester (trans/cis=1:5) (180 mg, 1.38 mmol), and PS—PPh₃ (loading2.02 mmol/g; 951 mg, 2.02 mmol) in dry THF (10 mL), cooled by ice/water,was added DIAD (295 μL, 303 mg, 1.50 mmol), then the cooling bath wasremoved, and the mixture was vortexed (220 rpm) for 2 d. The resin wasfiltered off and washed thoroughly with THF (7480 mL), the filtrate andwashings were combined, concentrated, and chromatographed on silica gel[Jones Flashmaster, 20 g/70 mL cartridge, eluting with CH₂Cl₂ (1-14)→5%EtOAc in CH₂Cl₂ (15-30)], fractions containing product were combined andchromatographed again under the same conditions. This material wassuspended in iPrOH (≈1.5 mL), heated to 75° C. for 10 min and cooled to−20° C. for 2 h. The solid was filtered off, washed with cold (−20° C.)iPrOH, and dried in vacuo, giving the title compound as white solid,trans/cis=5:1. ¹H NMR (CDCl₃, 400 MHz) δ 2.83-2.97 (m, 4H), 3.23-3.32(m, 1H), 3.79 (s, 3H), 5.50 (quint, J=8.7 Hz, 1H), 7.51 (s, 1H), 8.61(s, 1H). MS (ES+): m/z 391.9/393.9 (100/35) [MH⁺]. HPLC: t_(R)=3.5 min(OpenLynx, polar_(—)5 min).

Example 98cis-7-(3-Dimethylaminomethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Nitrogen was bubbled into a mixture of7-(3-dimethylaminomethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine(891.5 mg, 2.401 mmol),2-phenyl-7-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-quinoline (795mg, 2.40 mmol), Na₂CO₃ (634 mg, 5.98 mmol), and Pd(PPh₃)₄ (171 mg, 0.148mmol; 6 mol %) in DMF (40 mL)/water (8 mL) for 5 min at ambienttemperature, then the mixture was heated to 80° C. (bath temp.) for 4.5h. The solvents were evaporated, water was added, the mixture wasextracted with CH₂Cl₂ (4×30 mL), and the combined extracts were washedwith brine and dried over MgSO₄. The crude material (yellow oil) waschromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge,eluting with CH₂Cl₂ (1-28)→5% MeOH in CH₂Cl₂ (29-56)->10% MeOH in CH₂Cl₂(57-80)→10% MeOH in CH₂Cl₂ with 0.07M NH₃ (81-130)]. Mixed fractionswere chromatographed again [5 g/25 mL cartridge, eluting with CH₂Cl₂(1-5)→5% MeOH in CH₂Cl₂ (6-24)→10% MeOH in CH₂Cl₂ with 0.07M NH₃(25-40)]. One obtained the target compound as beige solid. ¹H NMR(CDCl₃, 400 MHz): δ=2.10-2.23 (m_(c), 2H), 2.27 (s, 6H), 2.35-2.46(m_(c), 1H), 2.49 (d, J=6.8 Hz, 2H), 2.77-2.86 (m_(c), 2H), 5.17 (brs,2H), 5.20-5.30 (m_(c), 1H), 7.31 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58(m, 2H), 7.70 (dd, J=1.6, 8.4 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.94 (d,J=8.1 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.30 (brs,1H), 8.36 (s, 1H). ¹³C NMR (CDCl₃, 100.6 MHz, DEPT135): δ=27.13 (+),36.50 (2C, −), 45.26 (+), 45.73 (2C, +), 66.10 (−), 101.20 (C_(quart)),116.07 (C_(quart)), 119.00 (+), 120.74 (+), 125.98 (C_(quart)), 127.38(+), 127.55 (2C, +), 128.28 (+), 128.47 (+), 128.86 (2C, +), 129.52 (+),136.45 (C_(quart)), 136.55 (+), 139.41 (C_(quart)), 148.51 (C_(quart)),150.92 (C_(quart)), 152.04 (+), 156.99 (C_(quart)), 158.13 (C_(quart)).MS (ES+): m/z 449.2 (23) [MH⁺], 404.1 (4) [MH⁺—HN(CH₃)₂], 338.2 (4)[MH⁺—C₄H₅CH₂N(CH₃)₂]. HPLC: t_(R)=2.0 min (OpenLynx, polar_(—)5 min).

7-(3-Dimethylaminomethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-s]pyrimidin-4-ylamine

A mixture of cis-toluene-4-sulfonic acid3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutylmethyl ester(1.50 g, 3.01 mmol) and a 2M solution of dimethylamine in THF (30 mL, 60mmol) was heated to 55° C. for 23 h in a glass pressure tube. Thesolvent was evaporated, water was added, the mixture was extracted withCH₂Cl₂ (4×40 mL), and the extracts were washed with brine and dried overMgSO₄. The crude material was chromatographed on silica gel [JonesFlashmaster, 10 g/70 mL cartridge, eluting with CH₂Cl₂ (1-8)→5% MeOH inCH₂Cl₂ (9-24)→10% MeOH in CH₂Cl₂ (25-35)→10% MeOH in CH₂Cl₂ with 0.07MNH₃ (36-48)], fractions containing product were combined and dried invacuo. One obtained the title compound as brown solid. ¹H NMR (CDCl₃,400 MHz): δ=2.01-2.11 (m_(c), 2H), 2.26 (s, 6H), 2.30-2.43 (m_(c), 1H),2.46 (d, J=6.8 Hz, 2H), 2.69-2.77 (m_(c), 2H), 5.05-5.15 (m_(c), 1H),5.59 (brs, 2H), 7.20 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 372.1 (20)[MH⁺]. HPLC: t_(R)=1.3 min (OpenLynx, polar_(—)5 min).

cis-Toluene-4-sulfonic acid3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutylmethyl ester

Into the suspension ofcis-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol(1322 mg, 3.842 mmol) in CH₂Cl₂ (55 mL) was added dropwise pyridine(6749 μL, 21.7 eq.) at −78° C. under N₂ over 10 min followed by theaddition of a solution of Ts₂O (1568 mg, 1.25 eq.) in CH₂Cl₂ (35 mL)over 20 min. After stirring at rt for 3 h, the reaction mixture wastreated with saturated NaHCO₃, and the organic phase was separated. Theaqueous phase was extracted with CH₂Cl₂ (50 mL). The combined organicphases were washed with H₂O (2×100 mL) and brine (100 mL), and driedover MgSO₄. After removing the solvent, a brown paste (2050 mg) wasobtained. The brown paste was purified by chromatography on silica gel(50 g pre-packed column) and eluted with CH₂Cl₂ (600 mL), 2% MeOH/CH₂Cl₂(600 mL), and 4% MeOH/CH₂Cl₂ (600 mL) to obtain the title compound as alight-brown foam. ¹H NMR (CDCl₃, 400 MHz): δ=2.20-2.28 (m, 2 H), 2.47(s, 3 H), 2.47-2.52 (m, 1 H), 2.57-2.64 (m, 2 H), 4.12-4.13 (d, 2 H,J=5.2 Hz), 5.07-5.11 (m, 1 H), 5.63 (brs, 2 H), 7.14 (s, 1 H), 7.37-7.39(d, 2 H, J=7.6 Hz), 7.81-7.84 (m, 2 H), 8.22 (s, 1 H). MS (ES+): m/z498.9 (100) [MH⁺]. HPLC: t_(R)=3.0 min (OpenLynx, polar_(—)5 min).

cis-[3-(4-Amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol

Gaseous ammonia (from a lecture bottle) was bubbled into a suspension ofcis-[3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol(406.8 mg, 1.12 mmol) in dioxane (10 mL) and iPrOH (10 mL) in a Parrbomb, cooled by dry ice/acetone, for 5 min, then the vessel was sealedand heated to 90° C. overnight. LC/MS after 17 h indicated incompleteconversion. More ammonia was bubbled into the mixture, and heating to90° C. was continued. After 1d, conversion was complete. The solventswere evaporated, water was added to the residue, and the pale yellowsolid was filtered off and dried in vacuo to give the title compound asa pale yellow solid. The compound was used in the next step withoutfurther purification. The aqueous filtrate was extracted with CH₂Cl₂(3×20 mL), the combined extracts were dried over MgSO₄, filtered andconcentrated to give a yellow oil that slowly solidified. Purificationby HPLC gave analytically pure material. ¹H NMR (CDCl₃, 400 MHz):δ=2.40-2.57 (m, 4H), 2.57-2.66 (m, 2H), 3.73 (d, J=4.4 Hz, 2H), 5.03(quint, J=8.4 Hz, 1H), 5.62 (brs, 2H), 7.21 (s, 1H), 8.26 (s, 1H). ¹³CNMR (DMSO-d₆, 100.6 MHz, DEPT135): b=29.96 (+), 32.70 (2C, −), 44.42(+), 50.25 (C_(quart)), 64.16 (−), 102.98 (C_(quart)), 126.94 (+),149.41 (C_(quart)), 151.72 (+), 157.13 (C_(quart)). MS (ES+): m/z 345.0(100) [MH⁺]. HPLC: t_(R)=1.7 min (OpenLynx, polar_(—)5 min). C₁₁H₁₃IIN₄O⅔ H₂O: C: calc. 37.10, found 36.92; H: calc. 4.06, found 3.88; N: calc.15.73, found 16.07.

cis-[3-(4-Chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol

To a solution ofcis-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid methyl ester (2.15 g, 5.49 mmol) in CH₂Cl₂ (85 mL), cooled by dryice/acetone, was added DIBAL (1M in toluene, 12.4 mL, 12.4 mmol) over 5min. Note that the ester started precipitating at the low temperature;but upon adding the DIBAL solution, a clear, pale yellow solutionformed. After 50 min, the dry ice/acetone bath was replaced with andice/water bath. The reaction was quenched 2.5 h later by addingNa₂SO₄.10 H₂O. A very slow gas evolution occurred, even with vigorousstirring or sonication. MeOH (2 mL) was added at ambient temperature,and a precipitate slowly formed, which was filtered off and washed with150 mL of 10% MeOH in CH₂Cl₂. The combined filtrate and washings wereconcentrated, the resulting solid was suspended in 80 mL of 10%MeOH/CH₂Cl₂, heated briefly to 45° C., and cooled to −20° C. overnight.The white solid was filtered off and dried in vacuo, yielding the titlecompound. The aluminum-containing precipitate was suspended in potassiumsodium tartrate solution and extracted with CH₂Cl₂ (3×100 mL), thecombined extracts were dried over MgSO₄, filtered, and combined with themother liquor of the white solid. This material was adsorbed ontoHydromatrix and chromatographed on silica gel [Jones Flashmaster, 10g/70 mL cartridge, eluting with CH₂Cl₂ (1-7)→CH₂Cl₂:EtOAc 5:1(8-32)→CH₂Cl₂:EtOAc 4:1 (33-43)] to give a second crop of the titlecompound. ¹H NMR (CDCl₃, 400 MHz): δ=1.79 (brs, 1H), 2.40-2.53 (m, 3H),2.59-2.71 (m, 2H), 3.74 (brs, 2H), 5.13-5.23 (m_(c), 1H), 7.60 (s, 1H),8.60 (s, 1H). MS (ES+): m/z 364.0/366.0 (100/40) [MH⁺]. HPLC: t_(R)=2.9min (OpenLynx, polar_(—)5 min).

cis-3-(4-Chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid methyl ester

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (preparedaccording to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7),1984-92) (2.10 g, 7.51 mmol), trans-3-hydroxycyclobutanecarboxylic acidmethyl ester (trans/cis=5:1) (1.11 g, 8.53 mmol), and PS—PPh₃ (loading2.21 mmol/g; 6.80 g, 15.0 mmol) in dry THF (80 mL), cooled by ice/water,was added DIAD (2.20 mL, 2.26 g, 11.2 mmol), then the cooling bath wasremoved, and the mixture was vortexed (150 rpm) overnight. The resin wasfiltered off and washed thoroughly with THF (≈400 mL), the filtrate andwashings were combined, concentrated, and chromatographed on silica gel[Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH₂Cl₂ (1-16)→5%EtOAc in CH₂Cl₂ (17-40)]. Fractions 3-32 were combined, concentrated,and suspended in iPrOH (10 mL). The suspension was heated to 85° C. for20 min and cooled to −20° C. for 2 h, the solid was filtered off, washedwith cold (−20° C.) iPrOH, and dried in vacuo. One obtained the titlecompound as white solid. Analytically pure material with cis/trans=50:1had a melting point of 168-169° C. ¹H NMR (CDCl₃, 400 MHz): δ=2.66-2.78(m, 2H), 2.81-2.93 (m, 2H), 3.06 (quint, J=8.7 Hz, 1H), 3.76 (s, 3H),5.32 (quint, J=8.7 Hz, 1H), 7.68 (s, 1H), 8.60 (s, 1H). ¹³C NMR (CDCl₃,100.6 MHz, DEPT135): δ=30.93 (+), 34.09 (2C, −), 44.65 (+), 51.58(C_(quart)), 52.19 (+), 117.07 (C_(quart)), 131.87 (+), 150.48(C_(quart)), 150.72 (+), 152.69 (C_(quart)), 174.31 (C_(quart)). MS(ES+): m/z 391.9/393.9 (100/38) [MH⁺]. HPLC: t_(R)=3.5 min (OpenLynx,polar_(—)5 min). C₁₂H₁₁ClIN₃O₂ (391.60): C: calc. 36.81, found36.88/36.78; H: calc. 2.83, found 2.81/2.76; N: calc. 10.73, found10.59/10.50.

trans-3-Hydroxycyclobutanecarboxylic acid methyl ester

To a solution of trans-3-acetoxycyclobutanecarboxylic acid methyl ester(trans/cis=5:1) (4.70 g, 27.3 mmol) in dry methanol (45 mL) was addedsodium methoxide (25 wt % solution in MeOH, 0.62 mL, 2.7 mmol), and thesolution was stirred at ambient temperature. More NaOMe solution (0.31mL, 2.4 mmol) was added after 1 h and 2 h, and stirring was continuedovernight. Most of the methanol was evaporated, water was added (≈100mL), and the mixture was extracted with CH₂Cl₂ (6×60 mL). The combinedorganic layers were washed with NaHCO₃ solution and brine, dried overMgSO₄, filtered and concentrated (vacuum down to mbar) to give the titlecompound as brown oil, trans/cis=5:1 based on ¹H NMR. The material thusobtained was used without further purification. ¹H NMR (CDCl₃, 400 MHz)δ 2.17-2.27 (m, 2H), 2.54-2.64 (m, 2H), 3.00-3.09 (m_(c), 1H), 3.70 (s,3H), 4.53-4.62 (m_(c), 1H).

trans-3-Acetoxycyclobutanecarboxylic acid methyl ester

A mixture of potassium acetate (16.9 g, 172 mmol) andcis-3-(toluene-4-sulfonyloxy)-cyclobutanecarboxylic acid methyl ester(9.8 g, 34 mmol; trans/cis=1:5) in dry DMF (50 mL) was heated to 120° C.for 21 h. DMF was partially distilled off (≈4=30 mL), water was added,and the mixture was extracted with EtOAc (6×50 mL). The combined organiclayers were washed with water (2×), brine, dried over MgSO₄, filteredand concentrated to give the title compound as brown oil, trans/cis=5:1based on ¹H NMR. The material thus obtained was used without furtherpurification.

trans-3-Acetoxycyclobutanecarboxylic acid methyl ester: ¹H NMR (CDCl₃,400 MHz) δ 2.044 (s, 3H), 2.31-2.41 (m, 2H), 2.62-2.71 (m, 2H),3.09-3.17 (m_(c), 1H), 3.71 (s, 3H), 5.15-5.23 (m_(c), 1H).

cis-3-Acetoxycyclobutanecarboxylic acid methyl ester: ¹H NMR (CDCl₃, 400MHz) δ 2.035 (s, 3H), 2.31-2.41 (m, 2H), 2.62-2.71 (m, 2H), 2.71-2.80(m_(c), 1H), 3.70 (s, 3H), 4.88-4.96 (m_(c), 1H).

cis-3-(Toluene-4-sulfonyloxy)-cyclobutanecarboxylic acid methyl ester

An ice bath cooled methylene chloride (80.0 mL) solution ofcis-3-hydroxy-cyclobutanecarboxylic acid methyl ester (4.00 g, 31.0mmol; predominantly cis) was charged with pyridine (3.00 mL, 37.0 mmol)and Ts₂O (11.1 g, 34.0 mmol). After 45 min, TLC analysis (EtOAc)revealed no starting material (KMnO₄ stain for alcohol sm). The reactionmixture was concentrated in vacuo, resuspended in ether (50.0 mL) andwashed with 0.5 N HCl (2×25 mL), saturated bicarbonate (2×25 mL), water(2×25 mL), brine (1×25 mL), and then dried over Na₂SO₄, filtered andconcentrated to yield the title compound as colorless oil, predominantlycis. ¹H NMR (400 MHz, CDCl₃): δ=2.44-2.55 (m, 7H), 2.56-2.65 (m, 1H),3.65 (s, 3H), 4.59-4.77 (m, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.77 (d, 2H,J=8.0 Hz).

cis-3-Hydroxycyclobutanecarboxylic acid methyl ester

A methanolic solution (210 mL) of 3-oxocyclobutanecarboxylic acid,cooled in an ice bath, was charged portionwise with sodium borohydride(4.66 g, 123 mmol). After stirring for 2 h, the reaction was deemedcomplete by TLC analysis (10% MeOH/CH₂Cl₂, KMnO₄ stain). The reactionwas charged with 2N HCl in ether until the pH of the solution becameacidic (pH=2). The reaction mixture was diluted with 400 mL of methanoland heated to 75° C. for 16 h. The reaction was concentrated in vacuo,resuspended in CH₂Cl₂ (100 mL), washed with water (2×50 mL), saturatedbicarbonate (1×50 mL), water (1×50 mL), and brine (1×50 mL), then driedover Na₂SO₄, filtered and concentrated to afford the desired product asan oil (predominantly cis). IR (film) 3406, 2989, 2949, 1727, 1720 cm⁻¹.¹H NMR (400 MHz, CDCl₃) δ 1.97 (d, 1H, J=7.2 Hz), 2.13-2.21 (m, 2H),2.56-2.64 (m, 3H), 3.67-3.70 (m, 3H), 4.17-4.20 (m, 1H).

3-Oxo-cyclobutanecarboxylic acid

3,3-Dimethoxy-cyclobutane-1,1-dicarboxylic acid diisopropyl ester (0.1mmol, 30 g) was refluxed in 20% HCl aqueous solution for 60 h. Part ofthe HCl aqueous solution was evaporated under high vacuum and lightbrown color oil remained. The oil was dissolved by EtOAc and washed bybrine. The organic layer was dried by NaSO₄, filtered, and evaporatedunder vacuum. The title compound was obtained as an off-white solidafter recrystallization from chloroform.

3,3-Dimethoxy-cyclobutane-1,1-dicarboxylic acid diisopropyl ester

A 1 L, two-necked flask containing 95% NaH (5.04 g, 210 mmol) wascharged with 75 mL of DMF, evacuated, placed under a nitrogen atm, andcooled in an ice bath. Diisopropyl malonate (34.0 mL, 191 mmol) wascarefully added dropwise via addition funnel under a positive flow ofnitrogen (reaction vented through a needle placed in a septum on thesecond neck of the flask). After the addition of the malonate, thesolution became very thick and yellow in color. After stirring for 1 h,the reaction was charged with 1,3-dibromo-2,2-dimethoxypropane (25.0 g,95.4 mmol) in one portion and the reaction was heated to 140° C. for 24h, upon which time the reaction became thick and orange in color.Saturated ammonium chloride (300 mL) was added and the mixture wasextracted with hexanes (3×, 500 mL). The organic layers were combined,washed with water (2×, 500 mL), saturated bicarbonate (2×, 500 mL),water (2×, 500 mL), and brine (1×, 500 mL), then dried over Na₂SO₄,filtered and concentrated to an oil. Short path distillation (4-5 torr,oil bath temperature at 60° C. to 143° C.) afforded the title compoundas a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, 12H, J=6.0 Hz), 2.70(s, 4H), 3.15 (s, 6H), 5.06 (m, 2H).

Example 997-Cyclopropylmethyl-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Following the general procedure for the Suzuki coupling,7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0mg, 0.299 mmol) was reacted with2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (104mg, 0.314 mmol), Na₂CO₃ (79.0 mg, 0.745 mmol) and Pd(PPh₃)₄ (21 mg,0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material waspurified by an SCX column (2 g/6 mL barrel) followed by columnchromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge,eluting with CH₂Cl₂ (1-14)→1% MeOH in CH₂Cl₂ (15-34)→2% MeOH in CH₂Cl₂(35-56)], yielding the title compound as an off-white yellow solid. ¹HNMR (CDCl₃, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39(m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52(m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.8Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz,1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). ¹³C NMR (CDCl₃, 100.6 MHz,DEPT135): δ=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (C_(quart)),115.67 (C_(quart)), 118.96 (+), 123.30 (+), 125.94 (C_(quart)), 127.46(+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+),136.50 (C_(quart)), 136.55 (+), 139.45 (C_(quart)), 148.52 (C_(quart)),150.97 (C_(quart)), 152.04 (+), 156.99 (C_(quart)), 158.12 (C_(quart)).MS (ES+): m/z 392.1 (100) [MH⁺], 338.2 (22) [MH⁺—C₄H₆]. HPLC: t_(R)=2.9min (OpenLynx, polar_(—)5 min).

7-Cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Gaseous ammonia (from a lecture bottle) was condensed into a suspensionof 4-chloro-7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(394.8 mg, 1.184 mmol) in dioxane (3 mL) and iPrOH (2 ml.) in a sealableglass tube, cooled by dry ice/acetone, until the volume increased by mL,then the tube was sealed and heated to 100° C. overnight. The solventswere evaporated, water was added, the mixture was extracted with CH₂Cl₂(3×20 mL), and the combined CH₂Cl₂ extracts were washed with brine,dried over MgSO₄, filtered and concentrated to give the title compoundas a white solid. ¹H NMR (CDCl₃, 400 MHz): δ=0.36-0.43 (m, 2H),0.58-0.66 (m, 2H), 1.19-1.29 (m, 1H), 4.03 (d, J=6.8 Hz, 2H), 5.63 (brs,2H), 7.19 (s, 1H), 8.27 (s, 1H). ¹³C NMR (CDCl₃, 100.6 MHz, DEPT135):δ=4.02 (2C, −), 11.28 (+), 48.46 (C_(quart)), 49.19 (−), 103.96(C_(quart)), 128.70 (+), 150.03 (C_(quart)), 152.05 (+), 156.88(C_(quart)). MS (ES+): m/z 315.1 (100) [MH⁺]. HPLC: t_(R)=2.3 min(OpenLynx, polar_(—)5 min).

4-Chloro-7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (preparedaccording to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7),1984-92) (419 mg, 1.50 mmol), cyclopropylmethanol (165 μL, 147 mg, 2.04mmol), and PS—PPh₃ (2.12 mmol/g; 1.41 g, 2.99 mmol) in dry THF (10 mL),cooled by ice/water, was added DIAD (440 μL, 452 mg, 2.23 mmol; 1.5equiv.), then the cooling bath was removed and the mixture was vortexedovernight. The resin was filtered off and washed thoroughly with THF,and the filtrate and washings were combined and concentrated.Chromatography of the crude material thus obtained on silica gel (JonesFlashmaster, 2 columns, 10 g/70 mL cartridge each, eluting with CH₂Cl₂)gave the title compound as an off-white solid. ¹H NMR (CDCl₃, 400 MHz):δ=0.41-0.47 (m, 2H), 0.63-0.69 (m, 2H), 1.20-1.31 (m, 1H), 4.12 (d,J=7.2 Hz, 2H), 7.52 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 333.9/335.9(100/38) [MH⁺]. HPLC: t_(R)=3.7 min (OpenLynx, polar_(—)5 min).

Example 1007-Cyclobutyl-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Following the general procedure for the Suzuki coupling,7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg,0.4536 mmol) was reacted with2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline(150.2 mg, 0.4533 mmol), Na₂CO₃ (120 mg, 1.13 mmol) and Pd(PPh₃)₄ (32mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material waspurified by column chromatography on silica gel [Jones Flashmaster, 10g/70 mL cartridge, eluting with CH₂Cl₂ (1-12)→1% MeOH in CH₂Cl₂(13-37)→2% MeOH in CH₂Cl₂ (38-61)], yielding the title compound as apale yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ=1.88-2.00 (m, 2H),2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd,J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H),8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s,1H). ¹³C NMR (CDCl₃, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +),48.26 (+), 101.15 (C_(quart)), 115.99 (C_(quart)), 118.99 (+), 120.86(+), 125.97 (C_(quart)), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48(+), 128.87 (2C, +), 129.52 (+), 136.49 (C_(quart)), 136.55 (+), 139.43(C_(quart)), 148.52 (C_(quart)), 150.79 (C_(quart)), 151.97 (+), 156.97(C_(quart)), 158.12 (C_(quart)). MS (ES+): m/z 392.1 (17) [MH⁺], 338.2(22) [MH⁺-cyclobutene]. HPLC: t_(R)=3.0 min (OpenLynx, polar_(—)5 min).

7-Cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Gaseous ammonia (from a lecture bottle) was condensed into a suspensionof 4-chloro-7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (70.7 mg,0.8115 mmol) in dioxane (2 mL) and iPrOH (2 mL) in a sealable glasstube, cooled by dry ice/acetone, until the volume increased by ≈2 mL,then the tube was sealed and heated to 100° C. overnight. The solventswere evaporated, water was added, the mixture was extracted with CH₂Cl₂(3×30 mL), and the combined CH₂Cl₂ extracts were washed with brine,dried over MgSO₄, filtered and concentrated to give the title compoundas a white solid. ¹H NMR (CDCl₃, 400 MHz): δ=1.83-1.95 (m, 2H),2.34-2.47 (m, 2H), 2.48-2.58 (m, 2H), 5.22 (quint, J=8.7 Hz, 1H), 5.63(brs, 2H), 7.26 (s, 1H), 8.26 (s, 1H). ¹³C NMR (CDCl₃, 100.6 MHz,DEPT135): δ=14.92 (−), 31.05 (2C, −), 48.50 (+), 48.82 (C_(quart)),104.11 (C_(quart)), 126.39 (+), 149.82 (C_(quart)), 152.00 (+), 156.94(C_(quart)). MS (ES+): m/z 315.0 (100) [MH⁺]. HPLC: t_(R)=2.4 min(OpenLynx, polar_(—)5 min).

4-Chloro-7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (preparedaccording to: L. B. Townsend et al. J. Med. Chem. 1990, 33 (7), 1984-92)(419 mg, 1.50 mmol), cyclobutanol (160 μL, 147 mg, 2.04 mmol), andPS—PPh₃ (2.12 mmol/g; 1.41 g, 2.99 mmol) in dry THF (10 mL), cooled byice/water, was added DIAD (440 μL, 452 mg, 2.23 mmol; 1.5 equiv.), thenthe cooling bath was removed and the mixture was vortexed overnight. Theresin was filtered off and washed thoroughly with THF, and the filtrateand washings were combined and concentrated. The crude material thusobtained was chromatographed on silica gel (Jones Flashmaster, 2columns, 10 g/70 mL cartridge each, eluting with CH₂Cl₂) to give a 10:1mixture of the title compound and4-chloro-7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (videsupra for a separate synthesis) as an off-white solid. ¹H NMR (CDCl₃,400 MHz): δ=1.88-2.01 (m, 2H), 2.41-2.65 (m, 4H), 5.28 (quint, J=8.6 Hz,1H), 7.58 (s, 1H), 8.60 (s, 1H). MS (ES+): m/z 333.9/335.9 (100/38)[MH⁺]. HPLC: t_(R)=3.8 min (OpenLynx, polar_(—)5 min).

Example 101cis-7-(3-Azetidin-1-ylmethylcyclobutyl)-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

To the DMF solution from the preparation ofcis-7-(3-azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminewere added2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (40mg, 0.12 mmol), Na₂CO₃ (27 mg, 0.25 mmol), Pd(PPh₃)₄ (7 mg, 0.006 mmol),and water (0.6 mL). The solution was purged with nitrogen for 10 min andheated to 80° C. for 16 h. To the cooled reaction solution was addedsat. Na₂CO₃ solution (10 mL), the mixture was extracted with EtOAc (3×20mL), the combined organic layers were washed with water (3×15 mL) andbrine, dried over MgSO₄, filtered, and concentrated to give a brown oil.Purification by HPLC gave the title compound as brown oil. ¹H NMR(CDCl₃, 400 MHz): δ=2.06-2.26 (m, 5 H), 2.56-2.57 (d, 2 H, J=6.2),2.71-2.77 (m, 2 H), 3.21-3.24 (m, 4 H), 5.17 (brs, 2 H), 5.19-5.26 (m,1H), 7.31 (s, 1 H), 7.46-7.56 (m, 3 H), 7.69-7.71 (dd, 1 H, J=1.6 & 8.4Hz), 7.90-7.94 (m, 2 H), 8.18-8.20 (m, 2 H), 8.26-8.29 (m, 2 H), 8.35(s, 1 H). MS (ES+): 461.2 [MH⁺]. HPLC: t_(R)=2.0 min (polar_(—)5 min).

cis-7-(3-Azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

The DMF (3 mL) solution of cis-toluene-4-sulfonic acid3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutylmethyl ester(see above for its preparation) (63 mg, 80% purity, 0.10 mmol) andazetidine (12 mg, 2 eq.) was stirred at 50° C. overnight in a sealedtube. The reaction mixture was used directly for further reaction. MS(ES+): 384.1 [MH⁺]. HPLC: t_(R)=1.4 min (polar_(—)5 min). For ¹H NMRanalysis, a small sample was taken out for HPLC purification. ¹H NMR(DMSO-d₆, 400 MHz): δ=1.99-2.06 (quintet, 2 H, J=6.9 Hz), 2.08-2.22 (m,3 H), 2.49-2.53 (m, 2 H), 2.54-2.56 (d, 2 H, J=6.4 Hz), 3.15-3.19 (d, 4H, J=7.2 Hz), 5.01-5.10 (quintet, 2 H, J=8.7 Hz), 6.69 (brs, 2 H), 7.80(s, 1 H), 8.16 (s, 1 H).

Example 102trans-3-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutanecarboxylicacid amide

A mixture oftrans-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid amide (119 mg, 0.333 mmol),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (133mg, 0.402 mmol), Na₂CO₃ (88.3 mg, 0.833 mmol), Pd(PPh₃)₄ (23.1 mg,0.0200 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for30 min and heated to 80° C. for 22 h. To the cooled reaction solutionwas added water (10 mL), the mixture was extracted with EtOAc (3×15 mL),the combined organic layers were washed with water (2×10 mL) and brine,dried over MgSO₄, filtered, and concentrated. The residue was trituratedwith MeOH to give the title compound as light yellow solid.Chromatography of the mother liquor on silica gel (8 g, eluting with2%→4%→6%→8%→10% MeOH in CH₂Cl₂) gave an additional batch. Both batchescontained a small amount of the corresponding cis isomer (see below forits independent synthesis). ¹H NMR (CDCl₃, 400 MHz): δ=2.70-2.78 (m, 2H), 2.97-3.08 (m, 2 H), 3.21-3.26 (m, 1 H), 5.66-5.72 (quintet, 1 H,J=8.4 Hz), 6.54 (brs, 2 H), 7.08 (s, 1 H), 7.59 (s, 1 H), 7.68-7.78 (m,3 H), 7.94-7.98 (m, 1 H), 8.12 (s, 1 H), 8.26-8.28 (d, 1 H, J=8.4 Hz),8.32-8.37 (m, 3 H), 8.48-8.53 (m, 2 H), 8.66-8.68 (d, 1 H, J=8.8 Hz). MS(ES+): 435.2 [MH⁺]. HPLC: t_(R)=2.3 min (polar_(—)5 min).

trans-3-(4-Amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid amide

Gaseous ammonia (from a lecture bottle) was condensed into a solution ofcis-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid methyl ester (see above for its preparation) (134.7 mg, 0.344 mmol)in CH₂Cl₂ (2 mL) and 2M NH₃ in iPrOH (4 mL) in a stainless steel Parrreactor, cooled by dry ice/acetone, until the volume approximatelydoubled, then the reactor was sealed, warmed to ambient temperatureovernight, and heated to 110° C. for 8 h. After cooling, the solventswere evaporated; the residue was washed with water and CH₂Cl₂ and driedin vacuo, yielding the title compound as beige solid. The aqueousfiltrate was concentrated, dissolved in EtOAc, washed with water andbrine, dried over MgSO₄, filtered and concentrated to give a secondbatch of the title compound as beige solid. Both batches were combinedfor the next step. ¹H NMR (DMSO-d₆, 400 MHz): δ=2.50 (m, 2 H), 2.66-2.74(m, 2 H), 2.97-3.02 (m, 1 H), 5.33-5.39 (quintet, 1 H, J=8.4 Hz), 6.60(brs, 2 H), 6.89 (s, 1 H), 7.39 (s, 1 H), 7.78 (s, 1 H), 8.09 (s, 1 H).MS (ES+): 357.9 [MH⁺]. HPLC: t_(R)=2.1 min (polar_(—)5 min).

Example 103cis-3-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutanecarboxylicacid amide

A mixture ofcis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid amide (131 mg, 0.367 mmol),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (146mg, 0.441 mmol), Na₂CO₃ (97.2 mg, 0.917 mmol), Pd(PPh₃)₄ (25.5 mg,0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for30 min and heated to 80° C. for 18 h. To the cooled reaction solutionwas added water (15 mL), the mixture was extracted with EtOAc (3×20 mL),the combined organic layers were washed with water (2×15 mL) and brine,dried over MgSO₄, filtered, and concentrated. The residue was trituratedwith MeOH to give the title compound as yellow solid. ¹H NMR (CDCl₃, 400MHz): δ=2.60-2.70 (m, 4 H), 2.84-2.90 (m, 1 H), 5.14-5.23 (quintet, 1 H,J=8.7 Hz), 6.31 (brs, 2 H), 6.92 (s, 1 H), 7.40 (s, 1 H), 7.50-7.62 (m,3 H), 7.78-7.82 (m, 2 H), 8.08-8.10 (d, 1 H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2 H), 8.49-8.51 (d, 1 H, J=8.4 Hz). MS (ES+): 435.0[MH⁺]. HPLC: t_(R)=2.4 min (polar_(—)5 min).

cis-3-(4-Amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid amide

Gaseous ammonia (from a lecture bottle) was condensed into a solution ofcis-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylicacid methyl ester (see above for its preparation) (200 mg, 0.511 mmol)in CH₂Cl₂ (3 mL) and 2M NH₃ in iPrOH (3 mL) in a stainless steel Parrreactor, cooled by dry ice/acetone, until the volume approximatelydoubled, then the reactor was sealed, warmed to ambient temperatureovernight, and heated to 115° C. for 8 h. After cooling, the solventswere evaporated; the residue was washed with water and CH₂Cl₂ and driedin vacuo, yielding the title compound as off-white solid. The aqueousfiltrate was extracted with EtOAc (2×60 mL), and the combined EtOAcextracts were dried over MgSO₄, filtered and concentrated to give asecond batch of the title compound as beige solid. Both batches werecombined for the next step. ¹H NMR (DMSO-d₆, 400 MHz): δ=2.64-2.70 (m, 4H), 2.88-2.96 (quintet, 1 H, J=8.5 Hz), 5.10-5.19 (quintet, 1 H, J=8.6Hz), 6.64 (brs, 2 H), 7.00 (s, 1 H), 7.48 (s, 1 H), 7.72 (s, 1 H), 8.19(s, 1 H). MS (ES+): 358.1 [MH⁺]. HPLC: t_(R)=1.7 min (polar_(—)5 min).

Example 104cis-{4-[4-Amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-methanol

Into the THF (1 mL) solution ofcis-4-[4-amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylicacid ethyl ester (13.3 mg, 0.0271 mmol) was added dropwise LiAlH₄ (1 Min THF, 203 μL, 0.75 eq.) at 0° C. under N₂. After stirring at rt for 2h, the reaction mixture was treated with saturated potassium sodiumtartarate solution (5 mL) and extracted with EtOAc (2×10 mL). Theextracts were washed with H₂O (10 mL) and brine (10 mL), and dried overMgSO₄. The drying agent was filtered off, and the filtrate wasconcentrated in vacuo. The crude material thus obtained was purified bypreparative TLC (silica gel, eluting with 7% MeOH/CH₂Cl₂) to yield thetitle compound as beige powder. ¹H NMR (CDCl₃, 400 MHz): δ=1.77-2.02 (m,9 H), 3.77-3.78 (d, 2 H, J=7.2 Hz), 4.77-4.82 (m, 1 H), 5.30 (brs, 2 H),7.24 (s, 1 H), 7.46-7.57 (m, 3 H), 7.67-7.70 (dd, 1 H, J=1.6 & 8.4 Hz),7.89-7.93 (m, 2 H), 8.18-8.20 (m, 2 H), 8.25-8.28 (m, 2 H), 8.36 (s, 1H). MS (ES+): 450.2 [MH⁺]. HPLC: t_(R)=2.5 min (polar_(—)5 min).

Example 105cis-4-[4-amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylicacid ethyl ester

A solution ofcis-4-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylicacid ethyl ester (16.2 mg 0.0391 mmol),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline(15.6 mg, 1.2 eq.), Pd(PPh₃)₄ (2.7 mg, 0.06 eq.) and Na₂CO₃ (10.4 mg,2.5 eq.) in DMF (2.5 mL)/H₂O (0.5 mL) was flushed with N₂ for 30 min atrt and heated at 80° C. for 16 h under nitrogen. After that time, thereaction mixture was treated with H₂O and extracted with EtOAc (3×10mL). The combined extracts were washed with H₂O (2×5 mL) and brine (5mL), and dried over MgSO₄. The drying agent was filtered off, thefiltrate was concentrated in vacuo, and the crude yellow oil waspurified by HPLC to obtain the title compound as yellow oil. ¹H NMR(CDCl₃, 400 MHz): δ=1.29-1.36 (t, 3 H, J=7.2 Hz), 1.74-2.09 (m, 6 H),2.34-2.41 (m, 2 H), 2.75 (m, 1 H), 4.19-4.25 (q, 2 H, J=7.2 Hz),4.77-4.85 (m, 1 H), 5.22 (brs, 2 H), 7.22 (s, 1 H), 7.46-7.57 (m, 3 H),7.68-7.70 (dd, 1 H, J=1.6 & 8.0 Hz), 7.89-7.93 (m, 2 H), 8.18-8.20 (dd,2 H, J=0.8 & 8.0 Hz), 8.25-8.27 (m, 2 H), 8.37 (s, 1 H). MS (ES+): 492.1[MH⁺]. HPLC: t_(R)=3.1 min (polar_(—)5 min).

cis-4-(4-Amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylicacid ethyl ester

Gaseous ammonia was bubbled into an'PrOH (1 mL) solution ofcis-4-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylicacid ethyl ester (30 mg, 70% pure by HPLC peak area, 0.048 mmol) in aglass pressure tube, cooled to −78° C. in a dry ice/acetone bath, for 15min. The tube was equipped with a Teflon washer, sealed and heated to110° C. for 7 h. After that time, the excess NH₃ and the solvent wereevaporated. The residue was used for the next reaction withoutpurification. A portion of above crude material were purified by HPLC togive the title compound as pale yellow oil. ¹H NMR (CDCl₃, 400 MHz):δ=1.31 (t, 3H, J=7.6 Hz), 1.63-1.98 (m, 6 H), 2.29-2.35 (m, 2 H), 2.73(m, 1 H), 4.22 (q, 2 H, J=7.6 Hz), 4.64-4.71 (m, 1 H), 5.58 (brs, 2 H),7.11 (s, 1 H), 8.26 (s, 1 H). MS (ES+): 415.0 [MH⁺]. t_(R)=2.7 min(polar_(—)5 min).

cis-4-(4-Chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylicacid ethyl ester

Into the THF (5 mL) solution of4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L.B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (140 mg, 0.500mmol), 4-hydroxycyclohexanecarboxylic acid ethyl ester (104 mg, 0.600mmol; Aldrich, cis/trans mixture), and PPh₃ (263 mg, 1.00 mmol) wasadded DIAD (203 mg, 1.00 mmol) dropwise at 0° C. under N₂ over 5 min.The reaction was then stirred at rt for 2 days. After that time, thesolvent was evaporated, and the residue was purified by chromatographyon silica gel, eluting with 200 mL of 5%, 10%, 20% and 30% EtOAc/hexaneto obtaincis-4-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylicacid ethyl ester as a white solid, which was further purified by HPLC.¹H NMR (CDCl₃, 400 MHz): δ=1.32 (t, 3H, J=7.2 Hz), 1.74-1.78 (m, 2 H),1.88-1.98 (m, 4 H), 2.33-2.36 (m, 2 H), 2.75-2.77 (m, 1 H), 4.23 (q, 2H, J=7.2 Hz), 4.73-4.81 (m, 1 H), 7.45 (s, 1 H), 8.60 (s, 1 H). MS(ES+): 433.9/435.9 [MH⁺]. HPLC: t_(R)=4.0 min (polar_(—)5 min).

Example 1067-Phenyl-5-(2-phenylquinolin-7-yl)-7H-pyrrolo[2,3-s]-pyrimidin-4-ylamine

Following the general procedure for the Suzuki coupling,5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (27 mg, 0.080 mmol)was reacted with2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline(26.5 mg, 0.080 mmol), Na₂CO₃ (22 mg, 0.21 mmol) and Pd(PPh₃)₄ (6 mg,0.005 mmol) in DMF (2.5 mL)/water (0.5 mL). The crude material waspurified by chromatography on an SCX column (1 g/6 mL barrel) followedby column chromatography on silica gel [Jones Flashmaster, 5 g/25 mLcartridge, eluting with CH₂Cl₂ (1-12) 1% MeOH in CH₂Cl₂ (13-33)→2% MeOHin CH₂Cl₂ (34-40)], yielding the title compound as an off-white solid.¹H NMR (CDCl₃, 400 MHz): δ=5.31 (brs, 2H), 7.38-7.42 (m, 1H), 7.43 (s,1H), 7.47-7.52 (m, 1H), 7.53-7.59 (m, 4H), 7.75 (dd, J=2.0, 8.4 Hz, 1H),7.75-7.79 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H),8.18-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.35-8.37 (m, 1H), 8.44 (s,1H). MS (ES+): m/z 414.0 (25) [MH⁺]. HPLC: t_(R)=3.4 min (OpenLynx,polar_(—)5 min).

5-Iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Gaseous ammonia (from a lecture bottle) was condensed into a suspensionof 4-chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (30 mg, 0.084mmol) in dioxane (2 mL) and iPrOH (2 mL) in a sealable glass tube,cooled by dry ice/acetone, until the volume increased by ≈2 mL, then thetube was sealed and heated to 100° C. overnight. The solvents wereevaporated, water was added, the mixture was extracted with CH₂Cl₂ (3×30mL), and the combined CH₂Cl₂ extracts were washed with brine, dried overMgSO₄, filtered and concentrated to give the title compound as a whitesolid. ¹H NMR (CDCl₃, 400 MHz): δ=5.69 (brs, 2H), 7.36 (s, 1H),7.36-7.41 (m, 1H), 7.49-7.55 (m, 2H), 7.60-7.64 (m, 2H), 8.33 (s, 1H).MS (ES+): m/z 337.0 (100) [MH⁺]. HPLC: t_(R)=2.8 min (OpenLynx,polar_(—)5 min).

4-Chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (preparedaccording to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7),1984-92) (280 mg, 1.00 mmol), phenylboronic acid (244 mg, 2.00 mmol),pyridine (165 μL, 161 mg, 2.04 mmol), and Cu(OAc)₂ (272 mg, 1.50 mmol)in CH₂Cl₂ (5 mL) was stirred under air at ambient temperature for 12 d.Aqueous ammonia (1 M) and CH₂Cl₂ were added, the solids were filteredoff, the layers of the filtrate were separated, the aqueous layer wasextracted with CH₂Cl₂ (2×30 mL), the combined CH₂Cl₂ layers were washedwith 1 M aqueous ammonia (2×), 2 M NaOH (2×), and brine and dried overMgSO₄. The crude material was adsorbed onto Hydromatrix andchromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge,eluting with CH₂Cl₂], yielding the title compound as off-white solid. ¹HNMR (CDCl₃, 400 MHz): δ=7.43-7.48 (m, 1H), 7.54-7.60 (m, 2H), 7.61-7.65(m, 2H), 7.69 (s, 1H), 8.68 (s, 1H). MS (ES+): m/z 355.9/357.9 (100/35)[MH⁺]. HPLC: t_(R)=3.8 min (OpenLynx, polar_(—)5 min).

Example 1071-Cyclobutyl-3-(2-phenylquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

Nitrogen was bubbled into a mixture of1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg,0.190 mmol),2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline(64.4 mg, 0.194 mmol), Na₂CO₃ (50.5 mg, 0.476 mmol), and Pd(PPh₃)₄ (13.7mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixturewas heated under nitrogen to 80° C. (bath temp.) for 17 h. The solventswere evaporated, water was added, the mixture was extracted with CH₂Cl₂(3×20 mL), and the combined extracts were washed with brine and driedover MgSO₄. MgSO₄ was filtered off, and the filtrate was concentratedand chromatographed on an SCX column (1 g/6 mL barrel). Theamine-containing fraction was adsorbed onto Hydromatrix andchromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge,eluting with CH₂Cl₂ (1-11)→1% MeOH in CH₂Cl₂ (12-28)→2% MeOH in CH₂Cl₂(29-46)], yielding the title compound as off-white solid. ¹H NMR (CDCl₃,400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (m_(c), 2H), 2.86-2.98 (m_(c),2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H),7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H),8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42(s, 1H), 8.49-8.52 (m, 1H). ¹³C NMR (CDCl₃, 100.6 MHz, DEPT135): δ=14.99(−), 29.91 (2C, −), 50.61 (+), 98.68 (C_(quart)), 119.59 (+), 126.53(+), 126.97 (C_(quart)), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +),129.00 (+), 129.53 (+), 134.83 (C_(quart)), 136.53 (+), 139.14(C_(quart)), 143.40 (C_(quart)), 148.22 (C_(quart)), 154.00 (C_(quart)),155.53 (+), 157.92 (C_(quart)), 158.18 (C_(quart)). MS (ES+): m/z 393.1(53) [MH⁺]. HPLC: t_(R)=3.1 min (OpenLynx, nonpolar_(—)5 min), 3.6 min(OpenLynx, polar_(—)5 min).

1-Cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

DIAD (440 μL, 452 mg, 2.23 mmol) was added to a cooled (ice/water)mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (472 mg, 1.81mmol, purchased from CNH Technologies, Inc.), PS-PPh₃ (Argonaut, loading2.21 mmol/g; 1.37 g, 3.03 mmol), and cyclobutanol (160 μL, 147 mg, 2.04mmol) in dry THF (15 mL), then the cooling bath was removed, and themixture was vortexed at ambient temp. for 16 d. More PS-PPh₃ (330 mg,0.729 mmol), DIAD (110 μL, 113 mg, 0.56 mmol), cyclobutanol (40 μL, 37mg, 0.51 mmol), and THF (5 mL) were added, and vortexing was continuedfor 4 d. The resin was filtered off, washed thoroughly with THF, and thecombined filtrate and washings were concentrated. The crude material wasadsorbed onto Hydromatrix and chromatographed on silica gel [JonesFlashmaster, 10 g/70 mL cartridge, eluting with CH₂Cl₂ (1-10)→2% MeOH inCH₂Cl₂ (11-24)→2.5% MeOH (25-30)→3% MeOH (31-44)]. Fr.15-27 werecombined and dried overnight in vacuo. One obtained the title compoundas a white solid. This material was used in the next step withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz): δ=1.81-2.00 (m, 2H),2.40-2.50 (m_(c), 2H), 2.72-2.84 (m_(c), 2H), 5.28-5.38 (m_(c), 1H),5.89 (brs, 2H), 8.32 (s, 1H). MS (ES+): m/z 316.0 (100) [MH⁺]HPLC:t_(R)=1.9 min (OpenLynx, nonpolar_(—)5 min), 2.7 min (OpenLynx,polar_(—)5 min).

3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(hydroxymethyl)cyclobutanol

To a solution of7-[8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline(3.2 g, 7.6 mmol) in THF-water mixture (100 mL, 3:1) were added NMO(1.94 g, 8.3 mmol) and potassium osmate dihydrate (0.14 g, 0.4 mmol).The reaction mixture was stirred at rt. After 20 h the reaction wasquenched with Na₂SO₃ (4.8 g, 38 mmol). The reaction mixture was dilutedwith EtOAc (250 mL) and washed with brine (2×100 mL). Part of thesolvent was removed and the organic phase was passed through celite,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The material wascarried on to the subsequent oxidation without further purification.

3-[8-chloro-1-(2-phenylquinolin-7-371)imidazo[1,5-a]pyrazin-3-yl]cyclobutanone

To a solution of3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(hydroxymethyl)cyclobutanol(7.6 mmol) in a THF-water mixture (200 mL, 3:1) was added NaIO₄(1.95 g,9.2 mmol) at 0° C. The reaction mixture was slowly warmed to rt andstirred for 4 h. The reaction mixture was diluted with EtOAc (200 mL)and washed with brine (2×75 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (Jones Flashmaster, 70 g/150 mLcartridge), eluting with 1:9 EtOAc/Hex→1:1 EtOAc/Hex to afford thedesired product as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 3.70-3.62(m, 2H), 3.94-3.85 (m, 3H), 7.56-7.45 (m, 4H), 7.64 (d, J=5.2, 1H),7.94-7.89 (m, 3H), 8.20-8.18 (m, 2H), 8.28 (dd, J=0.4 Hz, 8.4 Hz, 1H),8.52 (t, J=0.8 Hz, 1H). MS (ES+): m/z 425/427 (3/1) [MH⁺]. HPLC:t_(R)=3.7 min (Mass Directed purification system polar_(—)5 min method).

Example 1083-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone

To a solution of3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol(7.282 g, 17.69 mmol) in THF-water mixture (200 mL, 3:1) was added NaIO₄(4.542 g, 21.23 mmol) and the reaction was stirred at rt overnight. Thereaction mixture was diluted with DCM (500 mL) and the DCM layer wasseparated, washed with brine, dried over anhydrous Na₂SO₄ and evaporatedin vacuo. The crude product was purified by chromatography on silica gelusing DCM: MeOH as eluent (0%→2%) yielded the desired compound as ayellow solid. MS (ES+): m/z 406.15 [MH⁺]. HPLC: t_(R)=2.23 min(OpenLynx, polar_(—)5 min). ¹H NMR (400 MHz, CDCl₃) δ 3.60-3.36 (m, 2H),3.82-3.92 (m, 3H), 5.31 (br, 2H), 7.21 (dd, J=12.8, 4.8 Hz, 2H),7.48-7.56 (m, 3H), 7.91-7.98 (m, 3H), 8.18-8.20 (m, 2H), 8.28 (d, J=8.0Hz, 1H), 8.42 (s, 1H).

Method X1: General procedure for the synthesis of compounds of FormulaII-M.1 (compound of Formula II-M where Q¹=2-phenyl-quinolin-7-yl) fromcompounds of Formula II-L1 (Compound of Formula II-L whereQ¹=2-phenyl-quinolin-7-yl):

To a solution of 3-{(8-chloroimidazo)-2-phenylquinolin[1,5-a]pyrazin-3-yl}cyclobutanone (2.2 mmol, 953 mg) in DCE (0.2 M),HNR²R³ (3.4 mmol) and sodium triacetoxyborohydride (4.4 mmol, 930 mg)were added. The resulting mixture was stirred at rt overnight. Thereaction mixture was diluted with DCM (50 mL) and washed with saturatedNaHCO₃ (2×45 mL) and brine (45 mL). The solvent was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The resulting residue was purified bysilica gel chromatography, eluting with 0%→1% 2M NH₃ in MeOH/DCM toafford the desired product as a yellow solid.

To a solution of 3-{(8-chloroimidazo)-2-phenylquinolin[1,5-a]pyrazin-3-yl}cyclobutanone (60 mg, 0.1 mmol) in DCE (0.2M) wereadded HNR²R³ (0.2 mmol) and a catalytic amount of AcOH (10 μL). Themixture was stirred at rt for 30 min then charged with resin-boundtriacetoxyborohydride (0.2 mmol, 100 mg). Reaction mixture was stirredat it. After 16 h the solution was filtered through a Buchner funnel toremove the resin. The filtrate was concentrated and the residue wasdissolved in DCM (15 mL), washed with saturated NaHCO₃ (2×15 mL) andbrine (15 mL). The solvent was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography, eluting with 0%→1% 2M NH₃ in MeOH/DCM to afford thedesired product as a yellow solid.

Compounds of Formula II-M1 (compound of Formula II-M whereQ¹=2-phenyl-quinolin-7-yl) synthesized according to Method X1:

Compound Structure Name HNR²R³ Analytical data II-M1.1

[3-(8-Chloro-2- phenylquinolin imidazo [1,5-a]pyrazin-3-yl)-cyclobutyl]-dimethyl-amine

MS (ES+): m/z 454/456 (3/1) [MH⁺]; (CDCl₃, 400 MHz) δ 2.20 (s, 6H), 2.53(m, 2H), 2.69 (m, 2H), 2.88 (m, 1H), 3.49 (m, 1H), 5.27 (br, 2H), 7.35(d, J = 5.2 Hz, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.61 (d, J = 5.2 Hz,1H), 7.88 (m, 2H), 7.9 (d, J = 8.4 Hz, 1H), 8.19 (m, 2H), 8.25 (d, J =9.2 Hz, 1H), 8.49 (s, 1H). II-M1.2

[3-(8-Chloro-2- phenylquinolin imidazo [1,5-a]pyrazin-3-yl)-cyclobutyl]-diethyl-amine

MS (ES+): m/z 482/484 (3/1) [MH⁺]. II-M1.3

7-[8-Chloro-3(3-pyrrolidin- 1-yl-cyclobutyl)- imidazo[1,5-a]pyrazin-1-yl]-2-phenyl-quinoline

MS (ES+): m/z 482/484 (3/1) [MH⁺]. II-M1.4

{3-[8-Chloro-1-(2-phenyl- quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}- (2-methoxy-ethyl)-amine

MS (ES+): m/z 484/486 (3/1) [MH⁺]. II-M1.5

7-[8-Chloro-3-(3- morpholin-4-yl-cyclobutyl)- imidazo[1,5-a]pyrazin-1-yl]-2-phenyl-quinoline

MS (ES+): m/z 486/498 (3/1) [MH⁺]. II-M1.6

7-[8-Chloro-3-(4-methyl- piperazin-1-yl-cyclobutyl)-imidazo[1,5-a]pyrazin-1- yl]-2-phenyl-quinoline

MS (ES+): m/z 509/511 (3/1) [MH⁺]; (CDCl₃, 400 MHz) δ 2.30 (s, 3H),2.38-2.73 (m, 12H), 2.96-3.00 (m, 1H), 3.48- 3.54 (m, 1H), 7.35 (d, J =5.2 Hz, 1H), 7.47-7.48 (m, 1H), 7.52-7.55 (m, 2H), 7.60 (d, J = 5.2,1H), 7.88-7.92 (m, 3H), 8.18-8.20 (m, 2H), 8.26 (d, J = 8.8 Hz, 1H),8.50 (s, 1H). II-M1.7

4-(3-[8-Chloro-1-(2- phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-3-yl]-cyclobutyl)-piperazine- 1-carboxcylic acid benzyl ester

MS (ES+): m/z 629/631 (3/1) [MH⁺]. II-M1.8

7-[8-Chloro-3-(4-ethyl- piperazin-1-yl-cyclobutyl)-imidazo[1,5-a]pyrazin-1- yl]-2-phenyl-quinoline

MS (ES+): m/z 523/525 (3/1) [MH⁺]. II-M1.9

4-(3-[8-Chloro-1-(2- phenyl-quinolin-7-yl)- imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl)-piperazine- 1-carboxcylic acid tert-butyl ester

MS (ES+): m/z 595/597 (3/1) [MH⁺]. II-M1.10

1-(4-{3-[8-Chloro-1-(2- phenyl-quinolin-7-yl)- imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-iperazin-1- yl)-ethanone

MS (ES+): m/z 536/538 (3/1) [MH⁺]; (CDCl₃, 400 MHz) δ 2.09 (s, 3H),2.35-2.41 (m, 4H), 2.52-2.59 (m, 2H), 2.67-2.74 (m, 2H), 2.92-2.99 (m,1H), 3.46-3.64 (m, 5H), 7.37 (d, J = 5.2 Hz, 1H), 7.45-7.56 (m, 3H),7.59 (d, J = 4.8 Hz, 1H), 7.89- 7.92 (m, 3H), 8.18-8.20 (m, 2H), 8.27(d, J = 8.8 Hz, 1H), 8.51 (s, 1H).

Method X2: General procedure for the synthesis of compounds of FormulaI-L1 (compound of Formula I-L where Q¹=2-phenyl-quinolin-7-yl) fromcompounds of Formula II-M1 (Compound of Formula II-M whereQ1=2-phenyl-quinolin-7-yl):

Into a Parr pressure reactor a suspension of compound of Formula II-M1(0.105 g, 0.22 mmol) in i-PrOH and Tetrahydrofuran (10:1, 30 mL) wascooled to −78° C. and was charged with liquid NH₃ for 3-6 min. Theresulting solution was heated at 110° C. for 18-48 h. The Parr vesselwas cooled to −78° C. and the reaction slurry was transferred to a roundbottom flask and the solvent was removed in vacuo. The resulting mixturewas re-suspended in DCM and was filtered through a glass-fitted funnelto remove NH₄Cl. The reaction was chromatographed on SiO₂ eluting with1%→2%→3% 2M NH₃ in MeOH/DCM resulting in the desired yellow solid.

Method X3: General procedure for the synthesis of compounds of FormulaI-L1 (compound of Formula I-L where Q1=2-phenyl-quinolin-7-yl) fromcompounds of Formula I-K1 (Compound of Formula I-K whereQ1=2-phenyl-quinolin-7-yl):

To a solution of 3-{(8-iminoimidazo)-2-phenylquinolin[1,5-a]pyrazin-3-yl}cyclobutanone (2.2 mmol, 953 mg) in DCE (0.2M),HNR²R³ (3.4 mmol) and sodium triacetoxyborohydride (4.4 mmol, 930 mg)were added. The resulting mixture was stirred at it overnight. Thereaction mixture was diluted with DCM (50 mL) and washed with saturatedNaHCO₃ (2×45 mL) and brine (45 mL). The solvent was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The resulting residue was purified bysilica gel chromatography, eluting with 1%→2%→3% 2M NH₃ in MeOH/DCM toafford the desired product as a yellow solid, further purification viare-crystallization when necessary.

The following compounds of Formula I-L1 (compound of Formula I-L whereQ¹=2-phenyl-quinolin-7-yl) were synthesized according to either MethodX2 or X3:

Ex- Meth- ample Structure Name HNR²R³ Analytical Data od 109

3-[3-(4- Methyl- piperazin- 1-yl)- cyclobutyl]- 1-(2-phenyl- quinolin-7-yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 490 [MH⁺]; (400 MHz, (CD₃)₂SO δ 0.96 (t, J = 3.2 HZ, 3H),2.16-2.44 (m, 10H), 2.52-2.59 (m, 2H), 2.74-2.80 (m, 1H), 3.29 (m, 2H),3.59-3.64 (m, 1H), 6.19 (br, 2H), 7.08 (d, J = 4.8 Hz, 1H), 7.48- 7.58(m, 4H), 7.92 (d, J = 6.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.17 (d, J= 8.4 Hz, 1H), 8.23 (s, 1H), 8.29- 8.31 (m, 2H), 8.50 (d, J = 8.8 Hz,1H). X2 110

3-[3-(4- Ethyl- piperazin- 1-yl)- cyclobuty)]- 1-(2-phenyl- quinolin-7-yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 504 [MH⁺]; (400 MHz, CDCl₃) δ 1.10 (t, J = 6.8 Hz, 3H) 1.63(m, 4H), 2.48-2.58 (m, 6H), 2.96 (m, 1H), 3.49 (m, 3H), 5.19 (br, 2H),7.11 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.48-7.56 (m, 3H),7.91-7.94 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8 Hz, 1H), 8.39 (s,1H). X2 111

3-[3- (dimethyl- amino) cyclobutyl]- 1-(2-phenyl- quinolin-7-yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 435 [MH⁺]; (400 MHz, CDCl₃) δ 2.23 (s, 6H), 2.54 (m, 2H),2.69 (m, 2H), 2.90 (m, 1H), 3.45 (m, 1H), 5.27 (br, 2H), 7.11 (d, J =4.8 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.47-7.56 (m, 3H), 7.91-7.94 (m,3H), 8.18-8.20 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H). X2 112

3-[3- (diethyl- amino) cyclobutyl]- 1-(2-phenyl- quinolin-7- yl)imidazol[1,5-a] pyrazin-8- ylamine

(ES+): m/z 463 [MH⁺]; (400 MHz, CDCl₃) δ 1.02 (t, J = 7.2 Hz, 6H),2.52-2.69 (m, 8H), 3.29 (m, 1H), 3.43 (m, 1H), 5.29 (br, 2H), 7.09 (d, J= 4.0 Hz, 1H), 7.18 (d, J = 4.8, 1H), 7.47-7.55 (m, 3H), 7.89-7.93 (m,3H), 8.18 (m, 2H), 8.25 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H). X2 113

1-(2-Phenyl- quinolin-7- yl)-3-(3- pyrrolidin- 1-yl- cyclobutyl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 461 [MH⁺]; (400 MHz, CDCl₃) δ 1.80 (m, 4H), 2.54-2.69 (m,8H), 3.15 (m, 1H), 3.5 (m, 1H), 5.23 (br, 2H), 7.10 (d, J = 4.4 Hz, 1H),7.19 (d, J = 4.8, 1H), 7.47- 7.55 (m, 3H), 7.90-7.94 (m, 3H), 8.19 (m,2H), 8.26 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H). X2 114

3-[3-(2- Methoxy- ethylamino)- cyclobutyl]- 1-(2-phenyl- quinolin-7-yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 465 [MH⁺]; (400 MHz, CDCl₃) δ 2.39-2.46 (m, 2H), 2.84- 2.95(m, 5H), 3.28 (s, 3H), 3.47- 3.54 (m, 3H), 7.10 (d, J = 5.2 Hz, 1H),7.17 (d, J = 4.8, 1H), 7.47- 7.55 (m, 3H), 7.90-7.96 (m, 3H), 8.18-8.20(m, 2H), 8.26 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H). X2 115

3-(3- morpholin- 4-ylcyclo- butyl)- 1-(2-phenyl- quinolin-7- yl)imidazol[1,5-a] pyrazin-8- ylamine

(ES+): m/z 477 [MH⁺]; (400 MHz, CDCl₃) δ 2.43 (m, 4H), 2.51-2.54 (m,2H), 2.66-2.70 (m, 2H), 2.96 (m, 1H), 3.51 (m, 1H), 3.72-3.74 (m, 4H),5.23 (br, 2H), 7.12 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8, 1H),7.48-7.56 (m, 3H), 7.91-7.95 (m, 3H), 8.18-8.20 (m, 2H), 8.27 (d, J =8.4 Hz, 1H), 8.40 (s, 1H). X2 116

3-[(3-(4- tert butyl carboxylate piperazin- 1-yl) cyclobutyl]-1-(2-phenyl- quinolin- 7-yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 576 [MH⁺]; (400 MHz, CDCl₃) δ 1.46 (s, 9H), 2.34-2.37 (m,4H), 2.51-2.54 (m, 2H), 2.68- 2.70 (m, 2H), 2.94 (m, 1H), 3.44- 3.49 (m,5H), 5.29 (br, 2H), 7.11 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H),7.48-7.55 (m, 3H), 7.92-7.95 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8Hz, 1H), 8.40 (s, 1H). X2 117

3-[(3-(4- benzyl carboxylate piperazin- 1-yl) cyclobutyl]- 1-(2-phenyl-quinolin-7- yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 610 [MH⁺]; (400 MHz, CDCl₃) δ 2.35-2.38 (m, 4H), 2.51- 2.56(m, 2H), 2.66-2.72 (m, 2H), 2.93 (m, 1H), 3.47-3.55 (m, 5H), 5.13 (s,2H), 5.34 (br, 2H), 7.10 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 5.2, 1H),7.33-7.37 (m, 5H), 7.48- 7.55 (m, 3H), 7.93 (m, 3H), 8.19-8.21 (m, 2H),8.27 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H). X2 118

3-[(3-Cyclo- hexylamino- cyclobutyl)- 1-(2-phenyl- quinolin-7-yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 489 [MH⁺]; (400 MHz, CDCl₃) δ 1.11-1.25 (m, 6H), 1.71 (m,1H), 1.74 (m, 2H), 1.86 (m, 2H), 2.33-2.36 (m, 2H), 2.55 (m, 1H),2.88-2.91 (m, 2H), 3.43 (m, 1H), 3.55 (m, 1H), 5.29 (br, 2H), 7.10 (d, J= 4.8 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.47-7.55 (m, 3H), 7.90-7.96(m, 3H), 8.17-8.19 (m, 2H), 8.26 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H). X3119

1-(2- Phenyl- quinolin-7- yl)-3-(3- piperidin- 1-yl- cyclobutyl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 475 [MH⁺]; (400 MHz, CDCl₃) δ 1.45-1.46 (m, 2H), 1.57- 1.62(m, 4H), 2.31-2.39 (m, 4H), 2.50-2.55 (m, 2H), 2.65-2.72 (m, 2H), 2.88(m, 1H), 3.47 (m, 1H), 5.22 (br, 2H), 7.10 (d, J = 4.8 Hz, 1H), 7.20 (d,J = 5.2 Hz, 1H), 7.47-7.56 (m, 3H), 7.91-7.94 (m, 3H), 8.18-8.21 (m,2H), 8.26 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H). X3 120

3-[3-(1- Methyl- piperidin-4- ylamino)- cyclobutyl]- 1-(2-phenyl-quinolin-7- yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 504 [MH⁺]; (400 MHz, CDCl₃) δ 1.25-1.28 (m, 3H), 1.84 (m,2H), 2.00 (m, 2H), 2.28-2.37 (m, 5H), 2.56 (br, 1H), 2.85-2.92 (m, 4H),3.40-3.52 (m, 1H), 5.18 (br, 2H), 7.12 (d, J = 5.2 Hz, 1H), 7.18 (d, J =5.2 Hz, 1H), 7.48- 7.56 (m, 3H), 7.91-7.95 (m, 3H), 8.18-8.20 (m, 2H),8.27 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H). X3 121

1-(2- Phenyl- quinolin-7- yl)-3-[3- (tetrahydro- pyran-4- ylamino)-cyclobutyl]- imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 491 [MH⁺]; (400 MHz, CDCl₃) δ 1.26 (m, 2H), 1.40-1.49 (m,2H), 1.78-1.82 (m, 2H), 2.30- 2.38 (m, 2H), 2.77-2.79 (m, 1H), 2.86-2.92(m, 2H), 3.38-3.54 (m, 3H), 3.96-3.99 (m, 2H), 5.25 (br, 2H), 7.11 (d, J= 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.48-7.56 (m, 3H), 7.91-7.96(m, 3H), 8.19 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.41 (s, 1H). X3 122

3-(3-cyclo- butylamino- cyclobutyl)- 1-(2-phenyl- quinolin-7-yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 461 [MH⁺]; (400 MHz, CDCl₃) δ 1.65-1.78 (m, 4H), 2.17- 2.21(m, 2H), 2.34-2.37 (m, 2H), 2.83-2.86 (m, 2H), 3.33-3.42 (m, 3H), 5.29(br, 2H), 7.11 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.47-7.56(m, 3H), 7.90-7.96 (m, 3H), 8.18-8.20 (m, 2H), 8.26 (d, J = 8.8 Hz, 1H),8.41 (s, 1H). X3 123

3-(3-cyclo- pentylamino- cyclobutyl)- 1-(2-phenyl- quinolin-7-yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 475 [MH⁺]; (400 MHz, CDCl₃) δ 1.41-1.45 (m, 2H), 1.52- 1.56(m, 2H), 1.70-1.75 (m, 2H), 1.84-1.90 (m, 2H), 2.36-2.45 (m, 3H),2.90-2.97 (m, 2H), 3.17-3.21 (m, 1H), 3.46-3.54 (m, 1H), 5.57 (br, 2H),7.08 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 7.48- 7.57 (m, 3H),7.90-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.28 (d, J = 8.8 Hz, 1H), 8.40 (s,1H). X3 124

3-(3-cyclo- propylamino- cyclobutyl)- 1-(2-phenyl- quinolin-7-yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 447 [MH⁺]; (400 MHz, CDCl₃) δ 0.38-0.41 (m, 2H), 0.44- 0.47(m, 2H), 2.17-2.20 (m, 1H), 2.36-2.41 (m, 2H), 2.88-2.94 (m, 2H),3.43-3.55 (m, 2H), 5.30 (br, 2H), 7.12 (d, J = 5.2 Hz, 1H), 7.19 (d, J =5.2 Hz, 1H), 7.48-7.56 (m, 3H), 7.92-7.95 (m, 3H), 8.18-8.21 (m, 2H),8.27 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H). X3 125

3-[3- ((2R, 6S)- 2,6- Dimethyl- morpholin- 4-yl)- cyclobutyl]-1-(2-phenyl- quinolin-7- yl)imidazol [1,5-a] pyrazin-8- ylamine

(ES+): m/z 505 [MH⁺]; (400 MHz, CDCl₃) δ 1.17 (s, 3H), 1.18 (s, 3H),2.50-2.55 (m, 2H), 2.66-2.68 (m, 2H), 2.74-2.77 (mm 2H), 2.91 (m, 1H),3.49 (m, 1H), 3.65-3.70 (m, 2H), 5.24 (br, 2H), 7.11 (d, J = 5.2 Hz,1H), 7.20 (d, J = 5.2 Hz, 1H), 7.45-7.57 (m, 3H), 7.91- 7.94 (m, 3H),8.18-8.20 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H). X3 126

3-(3- Azetidin- 1-yl)- cyclobutyl)- 1-(2-phenyl- quinolin-7- yl)imidazol[1,5-a] pyrazin-8- ylamine

(ES+): m/z 447 [MH⁺]; (400 MHz, CDCl₃) δ 2.05-2.09 (m, 2H), 2.50- 2.60(m, 4H), 3.25-3.29 (m, 6H), 5.20 (br, 2H), 7.11 (d, J = 5.2 Hz, 1H),7.19 (d, J = 5.2 Hz, 1H), 7.48- 7.57 (m, 3H), 7.91-7.95 (m, 3H),8.18-8.20 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H). X3 127

3-(3-{4- [Bis-(4- fluoro- phenyl)- methyl]- piperazine- 1-yl)-cyclobutyl)- 1-(2-phenyl- quinolin-7- yl)imidazol [1,5-a] pyrazin-8-ylamine

(ES+): m/z 678 [MH⁺]; (400 MHz, CDCl₃) δ 2.29-2.54 (m, 10H), 2.64- 2.70(m, 2H), 2.96-2.30 (m, 1H), 3.45-3.50 (m, 1H), 4.22 (s, 1H), 5.20 (br,2H), 6.94-6.98 (m, 4H), 7.10 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 5.2 Hz,1H), 7.32-7.35 (m, 4H), 7.48-7.54 (m, 3H), 7.91-7.93 (m, 3H), 8.18- 8.20(m, 2H), 8.26 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H). X3 128

1-(2-Phenyl- quinolin-7- yl)-3-{3- [4-(prrimidin- 2-yloxy)- piperidin-1-yl]- cyclobutyl}- imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 569 [MH⁺]; (400 MHz, CDCl₃) δ 1.91-1.96 (m, 2H), 2.01- 2.10(m, 2H), 2.29-2.32 (m, 2H), 2.53-2.58 (m, 2H), 2.68-2.75 (m, 4H),2.96-2.98 (m, 1H), 3.46-3.50 (m, 1H), 5.08-5.10 (m, 1H), 5.22 (br, 2H),6.89-6.91 (m, 1H), 7.11 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H),7.46-7.56 (m, 3H), 7.91-7.95 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J =8.8 Hz, 1H), 8.39 (s, 1H). X3 129

4-(2-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- yclobutyl- amino}- ethyl)- piperazine- 1-carboxylic acid tert-butyl ester

(ES+): m/z 619 [MH⁺]; (400 MHz, CDCl3) δ 1.44 (s, 9H), 2.32-2.41 (m,6H), 2.48-2.51 (m, 2H), 2.72- 2.75 (m, 2H), 2.88-2.91 (m, 2H), 3.40-3.49(m, 6H), 5.20 (br, 2H), 7.12 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2, 1H),7.48-7.56 (m, 3H), 7.92-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.28 (d, J =8.8 Hz, 1H), 8.41 (s, 1H). X3 130

1-(2-Phenyl- quinolin-7- yl)-3-{3- [(thiophen- 2-ylmethyl)- amino]-cyclobutyl}- midazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 503 [MH⁺]; (400 MHz, (CDCl3) δ 2.35-2.38 (m, 2H), 2.86- 2.89(m, 2H), 3.42-3.51 (m, 2H), 4.01 (s, 2H), 5.23 (br, 2H), 6.94-6.95 (m,2H), 7.12 (m, 1H), 7.18-7.22 (m, 2H), 7.48-7.56 (m, 4H), 7.92- 7.95 (m,3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H). X3 131

1-(2-Phenyl- quinolin-7- yl)-3-(3- thio- morpholin- 4-yl- cyclobutyl)-imidazo[1,5- a]pyrazin-8- ylamine

(ES+): m/z 493 [MH⁺]; (400 MHz, CDCl3) δ 2.43-2.51 (m, 2H), 2.64- 2.73(m, 10H), 2.94-2.98 (m, 1H), 3.45-3.50 (m, 1H), 5.24 (br, 2H), 7.11 (d,J = 5.2 Hz, 1H), 7.19 (d, J = 5.2, 1H), 7.46-7.57 (m, 3H), 7.91-7.97 (m,3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H). X3 132

1-(2-Phenyl- quinolin-7- yl)-3-(3- thiazolidin- 3-yl- cyclobutyl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 479 [MH⁺]; (400 MHz, CDCl3) δ 2.55-2.62 (m, 2H), 2.69- 2.73(m, 2H), 2.89-2.92 (m, 2H), 3.09-3.12 (m, 2H), 3.27-3.31 (m, 1H),3.45-3.50 (m, 1H), 4.08 (s, 2H), 5.24 (br, 2H), 7.12 (d, J = 5.2 Hz,1H), 7.19 (d, J = 4.8, 1H), 7.46-7.57 (m, 3H), 7.92-7.96 (m, 3H),8.18-8.21 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.41 (s, 1H). X3 133

3-[3-(3- Morpholin- 4-yl-propyl- amino)- cyclobutyl]- 1-(2-phenyl-quinolin-7- yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 534 [MH⁺]. (400 MHz, CDCl3) δ 2.31-2.43 (m, 10H), 2.65-2.69(m, 2H), 2.86-2.91 (m, 2H), 3.42-3.49 (m, 2H), 3.69-3.71 (m, 4H), 5.19(br, 2H), 7.12 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 5.2, 1H), 7.48-7.57 (m,3H), 7.91-7.97 (m, 3H), 8.18-8.20 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H),8.41 (s, 1H). X3 134

1-(2-Phenyl- quinolin-7- yl)-3-[3- (4- pyrrolidin- 1-yl-piperidin-1-yl)- cyclobutyl]- imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 544 [MH⁺]. (400 MHz, CDCl3) δ 1.64-1.70 (m, 6H), 1.80- 1.94(m, 6H), 2.50-2.55 (m, 3H), 2.64-2.70 (m, 4H), 2.92-2.96 (m, 3H),3.46-3.49 (m, 1H), 5.19 (br, 2H), 7.11 (d, J = 4.8 Hz, 1H), 7.22 (d, J =5.2, 1H), 7.48-7.54 (m, 3H), 7.91-7.94 (m, 3H), 8.18-8.20 (m, 2H), 8.27(d, J = 8.4 Hz, 1H), 8.39 (s, 1H). X3 135

1-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- cyclobutyl}- piperidin- 4-ol

(ES+): m/z 491 [MH⁺]. (400 MHz, CDCl₃) δ 1.55-1.64 (m, 2H), 1.90- 1.94(m, 2H), 2.01-2.09 (m, 2H), 2.51-2.56 (m, 2H), 2.66-2.77 (m, 4H),2.91-2.93 (m, 1H), 3.45-3.49 (m, 1H), 3.72 (m, 1H), 5.22 (br, 2H), 7.11(d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 7.48-7.57 (m, 3H),7.91-7.95 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.39 (s,1H). X3 136

2-(4-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- cyclobutyl}- piperazin-1- yl)-ethanol

(ES+): m/z 519 [MH⁺]. (400 MHz, CDCl₃) δ 2.47-2.57 (m, 11H), 2.66- 2.72(m, 3H), 2.92-2.98 (m, 1H), 3.46-3.51 (m, 1H), 3.60-3.63 (m, 2H), 5.23(br, 2H), 7.11 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.48-7.56(m, 3H), 7.91-7.94 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H),8.39 (s, 1H). X3 137

3-{3-[4- (3H- imidazol-4- ylmethyl)- piperazin-1- yl]- cyclobutyl}-1-(2- phyenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 518 [MH⁺]. (400 MHz, CDCl₃) δ 2.09 (s, 3H), 2.36-2.42 (m,4H), 2.49-2.57 (m, 2H), 2.66- 2.73 (m, 2H), 2.94 (m, 1H), 3.46- 3.52 (m,3H), 3.26-3.65 (m, 2H), 5.23 (br, 2H), 7.12 (d, J = 4.8 Hz, 1H), 7.19(d, J = 5.2, 1H), 7.48- 7.56 (m, 3H), 7.92-7.95 (m, 3H), 8.19 (m, 2H),8.27 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H). X3 138

3-{3-[4-(2- Methoxy- ethyl)- piperazin- 1-yl]- cyclobutyl}- 1-(2-phenyl-quinolin-7- yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 534 [MH⁺]. (400 MHz, CDCl₃) δ 2.38-2.70 (m, 14H), 2.93- 2.99(m, 1H), 3.35 (s, 3H), 3.43-3.53 (m, 3H), 5.21 (br, 2H), 7.11 (d, J =4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.47-7.56 (m, 3H), 7.91-7.94 (m,3H), 8.18-8.20 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H). X3 139

1-(2-Phenyl- quinolin-7- yl)-3-[3-(4- pyrimidin-2- yl-piperazin- 1-yl)-cyclobutyl]- imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 554 [MH⁺]. (400 MHz, CDCl₃) δ 2.47-2.50 (m, 4H), 2.62- 2.54(m, 2H), 2.70-2.76 (m, 2H), 2.96-3.00 (m, 1H), 3.49-3.54 (m, 1H),3.84-3.87 (m, 4H), 5.26 (br, 2H), 6.49 (t, J = 4.8 Hz, 1H), 7.12 (d, J =5.2 Hz, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.48-7.57 (m, 3H), 7.92- 7.95 (m,3H), 8.19-8.21 (m, 2H), 8.28 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 4.8 Hz,2H), 8.38 (s, 1H). X3 140

1-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- cyclobutyl}- piperidine- 4-carboxylic acid ethyl ester

(ES+): m/z 547 [MH⁺]. (400 MHz, CDCl₃) δ 1.25 (t, J = 7.2 Hz, 3H),1.74-1.80 (m, 2H), 1.91-1.93 (m, 4H), 2.26-2.29 (m, 1H), 2.47-2.55 (m,2H), 2.65-2.72 (m, 2H), 2.87- 2.93 (m, 3H), 3.44-3.49 (m, 1H), 4.13 (q,J = 7.6 Hz, 2H), 5.23 (br, 2H), 7.11 (d, J = 5.2 Hz, 1H), 7.20 (d, J =5.2 Hz, 1H), 7.45-7.56 (m, 3H), 7.91-7.96 (m, 3H), 8.18-8.20 (m, 2H),8.27 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H). X3 141

2-(4-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- cyclobutyl}- piperazin-1- yl)-N- isopropyl- acetamide

(ES+): m/z 575 [MH⁺]. (400 MHz, CDCl₃) δ 0.88 (t, J = 6.8 Hz, 1H), 1.16(d, J = 6.4 Hz, 6H), 2.46-2.56 (m, 9H), 2.65-2.72 (m, 2H), 2.97- 3.01(m, 3H), 3.47-3.52 (m, 1H), 4.07 (m, 1H), 5.24 (br, 2H), 6.93 (br, 1H),7.11 (d, J = 4.4 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.46-7.56 (m, 3H),7.91-7.94 (m, 3H), 8.17- 8.20 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.39(s, 1H). X3 142

3-[3-(4- Methyl-[1, 4]diazepan- 1-yl)- cyclobutyl]- 1-(2- phenyl-quinolin-7- yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 504 [MH⁺]. (400 MHz, CDCl₃) δ 1.86 (m, 2H), 2.40-2.51 (m,5H), 2.64-2.72 (m, 10H), 3.12- 3.18 (m, 1H), 3.38-3.44 (m, 1H), 5.21(br, 2H), 7.11 (d, J = 5.2 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.46- 7.57(m, 3H), 7.91-7.95 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H),8.40 (s, 1H). X3 143

1-(2-Phenyl- quinolin-7- yl)-3-[3- (2,3,5,6- tetrahydro- [1,2′]bi-pyrazinyl- 4-yl)- cyclobutyl]- imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 554 [MH⁺]. (400 MHz, CDCl₃) δ 2.52-2.61 (m, 6H), 2.70- 2.76(m, 2H), 2.97-3.02 (m, 1H), 3.49-3.54 (m, 1H), 3.61-3.63 (m, 4H), 5.28(br, 2H), 7.12 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 7.46-7.56(m, 3H), 7.84 (m, 1H), 7.92-7.95 (m, 3H), 8.06 (m, 1H), 8.14 (m, 1H),8.18-8.21 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H). X3 144

(S)-1-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a]pyrazin- 3-yl]- cyclobutyl}- pyrrolidin- 3-ol

(ES+): m/z 477 [MH⁺]. (400 MHz, CDCl₃) δ 1.78 (m, 1H), 2.15-2.23 (m,2H), 2.37-2.38 (m, 2H), 2.55- 2.75 (m, 6H), 2.89-2.93 (m, 1H), 3.18-3.22(m, 1H), 3.48-3.52 (m, 1H), 4.35-4.38 (m, 1H), 5.24 (br, 2H), 7.11 (d, J= 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.47-7.56 (m, 3H), 7.90-7.94(m, 3H), 8.17-8.20 (m, 2H), 8.26 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H). X3145

(R)-1-{3- [8-Amino- 1-(2-phenyl- quinolin-7- yl)-imidazo [1,5-a]pyrazin- 3-yl]- cyclobutyl}- pyrrolidin- 3-ol

(ES+): m/z 477 [MH⁺]. (400 MHz, CDCl₃) δ 1.75-1.78 (m, 1H), 2.14- 2.38(m, 4H), 2.54-2.73 (m, 6H), 2.87-2.93 (m, 1H), 3.16-3.21 (m, 1H),3.47-3.52 (m, 1H), 4.35-4.38 (m, 1H), 5.25 (br, 2H), 7.11 (d, J = 4.8Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.47-7.56 (m, 3H), 7.91-7.94 (m, 3H),8.18-8.20 (m, 2H), 8.26 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H). X3 146

4-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- cyclobutyl}- piperazine-1- carboxylic acid dimethyl- amide

(ES+): m/z 547 [MH⁺]. (400 MHz, CDCl₃) δ 2.40-2.43 (m, 4H), 2.50- 2.57(m, 2H), 2.66-2.72 (m, 2H), 2.83 (s, 6H), 2.94-2.99 (m, 1H), 3.27-3.29(m, 4H), 3.47-3.52 (m, 1H), 5.29 (br, 2H), 7.11 (d, J = 4.8 Hz, 1H),7.20 (d, J = 5.2 Hz, 1H), 7.46-7.57 (m, 3H), 7.92-7.97 (m, 3H),8.18-8.21 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H). X3 147

(4-{3-[8- Amino-1- (2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-3-yl]- cyclobutyl}- piperazin-1- yl)-acetic acid ethyl ester

(ES+): m/z 562 [MH⁺]. (400 MHz, CDCl₃) δ 1.23-1.33 (m, 5H), 1.81- 1.84(m, 2H), 2.29-2.37 (m, 2H), 2.70-2.93 (m, 6H), 3.41-3.54 (m, 2H),4.07-4.15 (m, 4H), 5.22 (br, 2H), 7.12 (d, J = 4.8 Hz, 1H), 7.19 (d, J =4.8 Hz, 1H), 7.48-7.56 (m, 3H), 7.92-7.97 (m, 3H), 8.18-8.20 (m, 2H),8.27 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H). X3 148

3-{3-[4-(4- Fluoro- phenyl)- piperazin- 1-yl]- cyclobutyl}- 1-(2-phenyl-quinolin-7- yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 570 [MH⁺]. (400 MHz, CDCl₃) δ 2.53-2.61 (m, 6H), 2.70- 2.76(m, 2H), 3.00-3.05 (m, 1H), 3.13-3.15 (m, 4H), 3.49-3.54 (m, 1H), 5.36(br, 2H), 6.87-6.90 (m, 2H), 6.94-6.98 (m, 2H), 7.11 (d, J = 4.8 Hz,1H), 7.21 (d, J = 5.2 Hz, 1H), 7.48-7.56 (m, 3H), 7.91- 7.95 (m, 3H),8.18-8.20 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H). X3 149

3-{3- [Methyl- (1-methyl- piperidin- 4-yl)-amino]- cyclobutyl}-1-(2-phenyl- quinolin-7- yl)-imidazo [1,5-a] pyrazin-8- ylamine

(ES+): m/z 518 [MH⁺]. (400 MHz, CDCl₃) δ 1.70-1.75 (m, 4H), 1.96- 1.02(m, 2H), 2.21 (s, 3H), 2.31 (m, 3H), 2.50-2.57 (m, 3H), 2.63-2.70 (m,2H), 2.96-2.98 (m, 2H), 3.33- 3.49 (m, 2H), 5.21 (br, 2H), 7.11 (d, J =5.2 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.47-7.56 (m, 3H), 7.91-7.94 (m,3H), 8.18-8.20 (m, 2H), 8.27 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H). X3

Additionally, 3-[(3-(4-benzyl carboxylatepiperazin-1-yl)cyclobutyl]-1-(2-phenyl-quinolin-7-yl)imidazol[1,5-a]pyrazin-8-ylaminecould be prepared as follows: Prepared according to Method X1 whereHNR²R³ is equal to Cbz-piperazine followed by Method X2. The crudematerial was re-crystallized (DCM/Hex), yielding a yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 2.35-2.38 (m, 4H), 2.51-2.56 (m, 2H), 2.66-2.72 (m,2H), 2.93 (m, 1H), 3.47-3.55 (m, 5H), 5.13 (s, 2H), 5.34 (br, 2H), 7.10(d, J=5.2 Hz, 1H), 7.19 (d, J=5.2, 1H), 7.33-7.37 (m, 5H), 7.48-7.55 (m,3H), 7.93 (m, 3H), 8.19-8.21 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.40 (s,1H). MS (ES+): m/z 610 [MH⁺]. HPLC: t_(R)=2.13 min (Open-Lynx polar_(—)5min).

Additionally, 3-[(3-(4-tert butyl carboxylatepiperazin-1-yl)cyclobutyl]-1-(2-phenyl-quinolin-7-yl)imidazol[1,5-a]pyrazin-8-ylaminecould be prepared as follows: Prepared according to Method X1 whereHNR²R³ is equal to Cbz-piperazine followed by Method X2. The crudematerial was purified using Jones column (5 g, 25 mL) eluting with1%→3%→5% of MeOH/EtOAc, to give the desired yellow solid. ¹H NMR (400MHz, CDCl₃) δ 1.46 (s, 9H), 2.34-2.37 (m, 4H), 2.51-2.54 (m, 2H),2.68-2.70 (m, 2H), 2.94 (m, 1H), 3.44-3.49 (m, 5H), 5.29 (br, 2H), 7.11(d, J=5.2 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 7.48-7.55 (m, 3H), 7.92-7.95(m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J=8 Hz, 1H), 8.40 (s, 1H). MS(ES+): m/z 576 [MH+]. HPLC: tR=2.05 min (Open-Lynx polar_(—)5 min).

Example 1503-[(3-(piperazin-1-yl)cyclobutyl]-1-(2-phenyl-quinolin-7-yl)imidazol[1,5-a]pyrazin-8-ylamine

To a solution of 3-[(3-(4-benzyl carboxylatepiperazin-1-yl)cyclobutyl]-1-(2-phenyl-quinolin-7-yl)imidazol[1,5-a]pyrazin-8-ylamine(90 mg, 0.1 mmol) in DCM, 5 mL of 37% HCl was added and the resultingsolution was heated for 30 min at 60° C. The reaction mixture wasdiluted with water (5 mL) and washed with ether (2×10 mL), DCM (10 mL),the aqueous layer was basified with 3M NaOH and the solid was collectedby filtration. The solid was dissolved DCM (10 mL) and washed with brine(10 mL), the organic layer was dried over anhydrous Na₂SO₄ andconcentrated under in vacou, to afford the desired product as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 2.39-2.53 (m, 7H), 2.68 (m, 2H),2.90-2.94 (m, 5H), 3.49 (m, 1H), 5.19 (br, 2H), 7.11 (d, J=5.2 Hz, 1H),7.20 (d, J=5.2 Hz, 1H), 7.47-7.54 (m, 3H), 7.91-7.95 (m, 3H), 8.18-8.21(m, 2H), 8.27 (d, J=7.6 Hz, 1H), 8.39 (s, 1H). MS (ES+): m/z 476 [MH+].HPLC: tR=1.69 min (Open-Lynx polar_(—)5 min).

Method X4.1: General procedure for the synthesis of compounds of FormulaI-L1.2 (compound of Formula I-L where Q1=2-phenyl-quinolin-7-yl andNR²R³=

from reaction of Reagent A with compounds of Formula I-L1.1 (Compound ofFormula I-L where Q1=2-phenyl-quinolin-7-yl and NR²R³=

To a solution of1-(2-Phenyl-quinolin-7-yl)-3-(3-piperazin-1-yl-cyclobutyl)-imidazo[1,5-a]pyrazin-8-lamine(0.2 mmol, 100 mg) in DCE (0.1M), aldehyde (0.3 mmol) and sodiumtriacetoxyborohydride (0.42 mmol, 89 mg) were added. The resultingmixture was stirred at it overnight. The reaction mixture was dilutedwith DCM (30 mL) and washed with saturated NaHCO₃ (2×25 mL) and brine(25 mL). The solvent was dried over anhydrous Na₂SO₄ and concentrated invacuo. The resulting residue was purified by silica gel chromatography,eluting with 0%→3% 2M NH₃ in MeOH/DCM to afford the desired product as ayellow solid.

Method X4.2: General procedure for the synthesis of compounds of FormulaI-L1.2 (compound of Formula I-L where Q1=2-phenyl-quinolin-7-yl andNR²R³=

from reaction of Reagent B with compounds of Formula I-L1.1 (Compound ofFormula I-L where Q1=2-phenyl-quinolin-7-yl and NR²R³=

To a solution of3-[(3-(piperazin-1-yl)cyclobutyl]-1-(2-phenyl-quinolin-7-yl)imidazol[1,5-a]pyrazin-8-ylamine(50 mg, 0.11 mmol) in DCM (5 mL) were added DIPEA (0.81 mL, 0.6 mmol)and Reagent B (0.12 mmol). The resulting reaction mixture was stirredovernight at it. The mixture was diluted with DCM (10 mL) then washedwith saturated NaHCO₃ (10 mL) and brine (10 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacou. The resultingresidue was purified by silica gel chromatography, eluting with 0%-+3%2M NH₃ in MeOH/DCM to afford the desired product as a yellow solid.

The following compounds of Formula I-L1.2 (compound of Formula I-L whereQ1=2-phenyl-quinolin-7-yl and NR²R³=

were synthesized according to Method X4.1 or X4.2:

Example Structure Name Reagent/Method MS 1HNMR 151

3-(N,N- dimethylpiperazine-1- sulfonamide-4- ylcyclobutyl)-1-(2-phenyl-quinolin-7- yl)imidazol[1,5- a]pyrazin-8-ylamine

(ES+): m/z 583 [MH⁺]. (400 MHz, CDCl₃) δ 2.45-2.43 (m, 6H), 2.68- 2.70(m, 2H), 2.83 (s, 6H), 2.98 (m, 1H), 3.29- 3.31 (m, 4H), 3.49 (m, 1H),5.26 (br, 2H), 7.12 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H),7.48-7.56 (m, 3H), 7.91-7.95 (m, 3H), 8.18- 8.20 (m, 2H), 8.27 (d, J = 8Hz, 1H), 8.41 (s, 1H). 152

3[3-(4- Methanesulfonyl- piperazin-1-yl)- cyclobutyl)-1-(2-phenyl-quinolin-7-yl)- imidazol[1,5- a]pyrazin-8-ylamine

(ES+): m/z 554 [MH⁺]. (400 MHz, CDCl₃) δ 2.47-2.55 (m, 6H), 2.68- 2.74(m, 2H), 2.77 (s, 3H), 2.99 (m, 1H), 3.25- 3.27 (m, 4H), 3.51 (m, 1H),5.37 (br, 2H), 7.11 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8, 1H), 7.48-7.56 (m, 3H), 7.92-7.97 (m, 3H), 8.18-8.20 (m, 2H), 8.27 (d, J = 8.8 Hz,1H), 8.41 (s, 1H). 153

3-{3-[4-(2,2- Dimethyl-propyl)- piperazin-1-yl]- cyclobutyl}-1-(2-phyenyl-quinolin-7- yl)- imidazo[1,5a]pyrazin- 8-ylamine

(ES+): m/z 546 [MH⁺]. (400 MHz, CDCl₃) δ 0.86 (s, 9H), 2.01 (s, 2H),2.42-2.56 (m, 10H), 2.66-2.69 (m, 2H), 2.95 (m, 1H), 3.48 (m, 1H), 5.23(br, 2H), 7.10 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8, 1H), 7.48-7.56 (m,3H), 7.91-7.94 (m, 3H), 8.18-8.20 (m, 2H), 8.26 (d, J = 8.4 Hz, 1H),8.38 (s, 1H). 154

3-{3-[4-(3H-imidazol- 4-ylmethyl)-piperazin- 1-yl]-cyclobutyl}-1-(2-phyenyl-quinolin- 7-yl)- imidazo[1,5a]pyrazin- 8-ylamine

(ES+): m/z 556 [MH⁺]. (400 MHz, CDCl₃) δ 2.44-2.69 (m, 12H), 2.94- 2.98(m, 1H), 3.46-3.49 (m, 1H), 3.58 (s, 2H), 5.22 (br, 2H), 6.96 (s, 1H),7.11 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 5.2, 1H), 7.48-7.59 (m, 4H),7.91-7.93 (m, 3H), 8.19 (m, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H).

Additionally,3-[3-(4-Methyl-piperazin-1-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylaminecan be prepared as follows: A mixture of1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]imidazo[1,5-a]pyrazin-8-ylamine(206 mg, 0.5 mmol) and2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (182mg, 0.55 mmol) and cesium carbonate (326 mg, 1.0 mmol) in1,2-dimethoxyethane (10 mL) and water (2 mL) was evacuated and refilledwith nitrogen (3×), then tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol) was added, and the flask was again evacuated and refilledwith nitrogen (3×). The mixture was heated at 75° C. overnight. LC-MS(5127-03-1) showed the reaction was complete. The mixture wasconcentrated under reduced pressure, the residue was dissolved inMeOH-DMSO and purified by MDPS to give a yellow solid; LC-MS (ES, Pos.):490 [MH⁺]; ¹H NMR (CDCl₃, 400 MHz) δ 2.30 (s, 3H), 2.32-2.73 (m, 12H),2.96 (m, 1H), 3.49 (m, 1H), 5.19 (brs, 2H), 7.12 (d, J=5.0 Hz, 1H), 7.19(d, J=5.0 Hz, 1H), 7.46-7.56 (m, 3H), 7.91-7.97 (m, 3H), 8.19-8.21 (m,2H), 8.27 (d, J=8.6 Hz, 1H), 8.39 (s, 1H).

Example 1551-(4-Methyl-2-phenyl-quinolin-7-yl)-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine

A mixture of1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine(206 mg, 0.500 mmol) and4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline(190 mg, 0.550 mmol) and cesium carbonate (326 mg, 1.00 mmol) in1,2-dimethoxyethane (10.0 mL) and water (2.0 mL) was evacuated andrefilled with nitrogen (3×), then charged withtetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), and theflask was again evacuated and refilled with nitrogen (3×). The mixturewas heated at 75° C. overnight. The mixture was cooled to rt and dilutedwith ethyl acetate (30 mL), then washed with brine (15 mL); the organicphase was dried over anhydrous sodium sulfate, filtered, andconcentrated to afforded a yellow solid, which was purified by silicagel chromatography [CH₂Cl₂→5% MeOH/CH₂Cl₂→5% (2N NH₃-MeOH)/CH₂Cl₂, then10% (2N NH₃-MeOH)/CH₂Cl₂ to give the title compound as a yellow solid;LC-MS (ES, Pos.): 504 [MH⁺]; ¹H NMR (CDCl₃, 400 MHz) δ 2.30 (s, 3H),2.32-2.71 (m, 12H), 2.81 (d, J=0.9 Hz, 3H), 2.95 (m, 1H), 3.49 (m, 1H),5.19 (brs, 2H), 7.11 (d, J=5.0 Hz, 1H), 7.19 (d, J=5.0 Hz, 1H),7.45-7.55 (m, 3H), 7.75 (d, J=0.8 Hz, 1H), 7.94 (dd, J=8.6 Hz, 1.8 Hz,1H), 8.12 (d, J=8.6 Hz, 1H), 8.16-8.19 (m, 2H), 8.39 (d, J=1.4 Hz, 1H).

Example 1561-(8-Fluoro-2-phenyl-quinolin-7-yl)-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine

A solution of1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine(93 mg, 0.22 mmol),8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline(87 mg, 0.25 mmol) and cesium carbonate (88 mg, 0.27 mmol) in DME (3.33mL) and H₂O (0.67 mL) was degassed with N₂ for 10 minutes.Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) was added,and the reaction heated at 75° C. overnight. The reaction was allowed tocool to rt, poured into saturated NaHCO₃ solution (50 ml) and extractedwith ethyl acetate (3×50 ml). The combined organics were washed withbrine (3×50 ml), dried (MgSO₄), filtered and concentrated in vacuo.Flash chromatography (DCM stepping up to 5% MeOH in DCM) gave the titlecompound as an off-white solid; ¹H NMR (CDCl₃, 400 MHz) δ 8.27 (1H, d,J=8.6 Hz), 8.23 (2H, d, J=7.1 Hz), 7.99 (1H, d, J=8.8 Hz), 7.73-7.67(2H, m), 7.55-7.48 (3H, m), 7.16 (1H, d, 5.1 Hz), 7.06 (1H, d, J=5.1Hz), 3.46 (1H, m), 2.94 (1H, m), 2.71-2.32 (15H, m); MS (ES+): m/z508.03 [MH⁺]; HPLC: t_(R)=1.71 min (MicromassZQ, polar_(—)5 min).

The following compounds in Table ZA.1 were prepared according toprocedures described herein before:

MS Example Structure Name (M + H) 157

3-(3- Dimethylaminomethylcyclobutyl)- 1-(2-pyridin-2-yl-quinolin-7-yl)imidazo[1,5-a]pyrazin-8- ylamine 450.07 158

{3-[8-Amino-1-(2-pyridin-2-yl- quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}- methanol 423.07 159

3-[8-Amino-1-(4-methyl-2- phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]- cyclobutanol 422.01 160

{3-[8-Amino-1-(4-methyl-2- phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]- cyclobutyl}-methanol 436.03 161

3-(3-Azetidin-1-ylmethyl- cyclobutyl)-1-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[1,5- a]pyrazin-8-ylamine 474.98 162

{3-[8-Amino-1-(8-fluoro-2- phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]- cyclobutyl}-methanol 439.97 163

1-(4-{3-[8-Amino-1-(8-fluoro-2- phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]- cyclobutyl}-piperazin-1-yl)- ethanone535.98 164

1-(4-{3-[8-Amino-1-(4-methyl-2- phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]- cyclobutyl}-piperazin-1-yl)- ethanone532.03 165

3-[8-Amino-1-(8-fluoro-2-phenyl- quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol 425.94 166

4-{3-[8-Amino-1-(2-phenyl- quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}- piperazine-1-carboxylic acid methyl ester534.00 167

1-(4-{3-[8-Amino-1-(2-phenyl- quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}- piperazin-1-yl)-2-methyl-propan- 1-one546.02 168

3-{3-[(Furan-2-ylmethyl)-amino]- cyclobutyl}-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8- ylamine 487.96 169

1-(4-{3-[8-Amino-1-(2-phenyl- quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}- piperazin-1-yl)-2,2,2-trifluoro- ethanone571.97 170

1-(8-Fluoro-4-methyl-2-phenyl- quinolin-7-yl)-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]- imidazo[1,5-a]pyrazin-8-ylamine 522.06 171

7-Cyclobutyl-5-(4-methyl-2- phenyl-quinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamine 407.19

1-Iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine

A solution of 2N ammonia in isopropyl alcohol (350 mL) and THF (30 mL,0.4 mol) was added to8-chloro-1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazine(19.91 g, 0.04612 mol) in a Parr bomb and cooled to −78° C. Ammonia wasbubbled into the solution for 8-10 min. The bomb was sealed, stirred andheated to at 110° C. over 3 d. The solvent was then evaporated in vacuoand purified by flash silica gel chromatography (wetted with CHCl₃,dried loaded with silica, and eluted with 8% (7N NH₃) MeOH in CHCl₃),which afforded the title compound; ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (1H,d, J=5.01), 7.16 (1 H, d, J=6.25), 5.83 (2 H, s), 3.49 (1 H, m), 3.06 (1H, m), 2.76 (4 H, m), 2.64 (8 H, m), 2.46 (3 H, s); MS (ES+): m/z412.89/413.91 (50/10) [MH⁺]; HPLC: t_(R)=0.31 min. (OpenLynx, polar_(—)5min.).

8-Chloro-1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazine

1-Methyl piperazine (5.75 mL, 0.0514 mol) in 1,2-dichloroethane (1096.7mL, 13.892 mol) was added to3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (17.00 g,0.04892 mol) and sodium triacetoxyborohydride (21.8 g, 0.0978 mol). Thereaction stirred at it for 3 h. The reaction was concentrated, dissolvedin CH₂Cl₂, and then washed with saturated NaHCO₃ solution and brine. Theproduct was dried over sodium sulfate, filtered, and concentrated invacuo. The product was flushed through a quick silica gel plug (wettedwith 100% CHCl₃, eluted with 8% (7N NH₃) MeOH in CHCl₃), to afford thetitle compound; ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (1 H, d), 7.30 (1 H, d),3.42 (1H, m), 2.94 (1H, m), 2.65 (4 H, m), 2.44 (8 H, m), 2.32 (3H, s);MS (ES+): m/z 431.85/433.87 (100/45) [MH⁺]; HPLC: t_(R)=1.82 min.(OpenLynx, polar_(—)5 min.).

1-{4-[3-(8-Amino-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-piperazin-1-yl}-ethanone

1-{4-[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-piperazin-1-yl}-ethanone(13.2 g, 0.029 mol) was dissolved in isopropyl alcohol (100 mL) into aParr pressure reactor. The vessel was cooled to −78° C. and saturatedwith ammonia gas and sealed. The reaction was heated for 19 h at 110°C., at which point the reaction was cooled and the solvent concentratedin vacuo. The crude product was purified via silica gel chromatographyeluting with 5-10% MeOH (7M NH₃): CH₂Cl₂ to yield the title compounds asan off white solid; MS (ES+): m/z 440.89 (100) [MH⁺], 441.89 (20)[MH⁺⁺]; HPLC: t_(R)=0.46 min (OpenLynx, polar_(—)5 min); ¹H NMR (CDCl₃,400 MHz) δ 2.09 (s, 3 H) 2.28-2.48 (m, 6 H) 2.54-2.71 (m, 2 H) 2.80-2.99(m, 1 H) 3.27-3.43 (m, 1 H) 3.43-3.54 (m, 2 H) 3.56-3.70 (m, 2H) 7.02(d, J=5.05 Hz, 1 H) 7.16 (d, J=5.05 Hz, 2 H).

1-{4-[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-piperazin-1-yl}-ethanone

Into a RBF 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone(1.00 g, 0.0029 mol) and sodium triacetoxyborohydride (1.30 g, 0.006mol) were dissolved in 1,2-dichloroethane (65.0 mL) and a solution of1-acetylpiperazine (0.39 g, 0.003 mol) in 1,2-dichloroethane was addedto the reaction. The reaction mixture was stirred at room temperaturefor 2 h. The crude product was concentrated in vacuo and the dissolvedin CH₂Cl₂ (25.0 mL) and washed with saturated NaHCO₃ solution (1×40 mL).The product was dried with sodium sulfate and concentrated in vacuo toyield a light yellow solid; MS (ES+): m/z 459.84 (100) [MH⁺], 461.80(40) [MH⁺⁺⁺]; HPLC: t_(R)=1.81 min (OpenLynx, polar_(—)5 min); ¹H NMR(CDCl₃, 400 MHz) δ 2.04-2.15 (m, 3 H) 2.26-2.50 (m, 6 H) 2.55-2.72 (m, 2H) 2.83-2.99 (m, 1 H) 3.29-3.52 (m, 3 H) 3.56-3.67 (m, 2 H) 7.29 (d, 1H) 7.58 (d, 1 H).

3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone

A solution of3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethyl-cyclobutanol(4.08 g, 0.011 mol) in THF (120 mL) and water (40 mL) was charged withsodium periodate (2.8 g, 0.013 mol) at 0° C. The reaction warmed to itand stirred for 5 h. The reaction mixture was diluted with ethyl acetateand then washed with brine. The organic phase was dried over Na₂SO₄,filtered, and concentrated in vacuo to afford the title compound as ayellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (1 H, d, J=4.94), 7.32 (1H, d, J=4.98), 3.64 (5 H, m); MS (ES+): m/z 347.82/349.85 (100/30)[MH⁺]; HPLC: t_(R)=2.89 min. (OpenLynx, polar_(—)5 min.).

3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethyl-cyclobutanol

Under inert atmosphere N-iodosuccinimide (3.6 g, 0.016 mol) and3-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethyl-cyclobutanol(3.16 g, 0.012 mol) were dissolved in N,N-dimethylformamide (30 mL) andheated at 60° C. for 3.0 hours. The reaction mixture was thenconcentrated in vacuo to a dark oil and purified by HPFC Jones 20 gsilica gel column, eluting with 5% MeOH: CH₂Cl₂ to yield a light brownfluffy solid which was triturated with diethyl ether and hexanes toafford the title compound; MS (ES+): m/z 379.85 (100) [MH⁺], 381.80 (30)[MH⁺⁺⁺]; HPLC: t_(R)=2.30 min (OpenLynx, polar_(—)5 min).

3-(8-Chloro-imidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethyl-cyclobutanol

To a THF solution (170 mL) of8-chloro-3-(3-methylene-cyclobutyl)-imidazo[1,5-a]pyrazine (3.1 g, 14mmol), water (18 mL), 50% N-methylmorpholine-N-oxide in water (3.2 mL)and potassium osmate, dehydrate (200 mg, 0.70 mmol) were added and thereaction was allowed to stir at rt for 4 h. Sodium sulfite (8.0 g, 70.0mmol) was added to the reaction mixture and allowed to stir for 30 minat which point the reaction was concentrated in vacuo. The crude productwas extracted from the aqueous with EtOAc. The organics were washed withbrine and the combined aqueous washes were back extracted with EtOAc(5×50 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated in vacuo to yield the title compounds as asticky tan/off-white solid; MS (ES+): m/z 254.17 (100) [MH⁺], 256.19(50) [MH⁺⁺⁺]; HPLC: t_(R)=1.95 min (OpenLynx, polar_(—)5 min).

3-(8-Amino-1-iodo-imidazo pyrazin-3-yl)-cyclobutanol

In a Parr pressure reactor3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g,0.0119 mol) was dissolved with 2.0 M ammonia in isopropyl alcohol (40mL). The mixture was cooled to −20° C. and saturated with ammonia. Thereaction was heated at 110° C. for 63 h at which point it was cooled andconcentrated in vacuo. The crude product was purified using HPFC Jones25 gram silica gel column eluting with 5-8% MeOH: CH₂Cl₂ to yield thetitle compounds; MS (ES+): m/z 330.88 (100) [MH⁺], 331.89 (10) [MH⁺⁺];HPLC: t_(R)=0.48 min (OpenLynx, polar_(—)5 min); ¹H NMR (CDCl₃, 400 MHz)δ 2.55-2.76 (m, 2 H) 3.06-3.22 (m, 2 H) 3.32-3.50 (m, 1 H) 4.51-4.69 (m,1 H) 6.15 (br. s., 2 H) 7.24 (d, J=5.05 Hz, 1 H) 7.39 (d, J=5.05 Hz, 1H).

3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol

3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14mmol) was dissolved in a 1:1 mixture of methanol (35.0 mL) and CH₂Cl₂(35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0mmol) was added slowly, gas evolution was observed. After 4.5 h at rtunder nitrogen, the reaction was concentrated in vacuo. The crude mixwas dissolved in EtOAc and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified using HPFC Jones 50 gram silica gel column elutingwith 50% EtOAc: Hex to 100% EtOAc, to yield the title compound as alight yellow solid; MS (ES+): m/z 349.81 (100) [MH⁺], 351.50 (30)[MH⁺⁺⁺]; HPLC: t_(R)=2.49 min (OpenLynx, polar_(—)5 min); ¹H NMR (CDCl₃,400 MHz) δ 2.41-2.54 (m, 2 H) 2.78-3.05 (m, 1 H) 3.12-3.32 (m, 1 H)4.08-4.75 (m, 1 H) 5.30 (s, 1 H) 7.31 (d, J=5.05 Hz, 1 H) 7.57 (d,J=4.80 Hz, 1 H).

2-Phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline

A mixture of PdC1 ₂dppf.CH₂Cl₂ (28 mg, 0.038 mmol), dppf (21 mg, 0.038mmol), potassium acetate (370 mg, 3.77 mmol), bis(pinacolato)diboron(384 mg, 1.51 mmol), and trifluoromethanesulfonic acid2-phenylquinolin-7-yl ester (444.3 mg, 1.258 mmol) in dry 1,4-dioxane(10 mL) was heated under nitrogen to 80° C. for 27 h. After cooling toRT, water was added, the mixture was extracted with EtOAc (3×35 mL), thecombined extracts were washed with water and brine, dried over MgSO₄,filtered, and adsorbed onto Hydromatrix. Chromatography on silica gel[Jones Flashmaster, 10 g/70 mL cartridge, eluting with hexanes:EtOAc19:1→3 9:1→5:1] gave the title compound as pale yellow solid; ¹H NMR(CDCl₃, 400 MHz) δ 1.40 (s, 12H), 7.43-7.49 (m, 1H), 7.50-7.56 (m, 2H),7.81 (d, J=8.4 Hz, 1H), 7.88 (dd, J=8.0, 0.8 Hz, 1H), 7.92 (d, J=8.4 Hz,1H), 8.17-8.23 (m, 2H), 8.70 (s, 1H); MS (ES+): m/z 332.1 (100) [MH⁺];HPLC: t_(R)=4.4 min (OpenLynx, polar_(—)5 min).

Trifluoromethanesulfonic acid 2-phenylquinolin-7-yl ester

To a suspension of 2-phenylquinolin-7-ol (295.7 mg, 1.336 mmol) in drypyridine (285 μL, 279 mg, 3.5 mmol) and dry CH₂Cl₂ (12 mL), cooled byice/water, was added triflic anhydride (295 μL, 495 mg, 1.75 mmol)dropwise over 10 min. All material dissolved slowly; the solution, whichbecame dark red, slowly warmed up to ambient temperature. After 3 h, TLC(eluent CH₂Cl₂) indicated complete conversion of the starting material.Water (15 mL) was added, the layers were separated, the aqueous layerwas extracted with CH₂Cl₂ (3×15 mL), and the combined CH₂Cl₂ layers werewashed with water (2×) and brine and dried over MgSO₄. Filtration andconcentration gave a red oil that slowly solidified on standing. Thematerial thus obtained was used without further purification in the nextstep; ¹H NMR (CDCl₃, 400 MHz) δ 7.46 (dd, J=2.4, 8.8 Hz, 1H), 7.48-7.59(m, 3H), 7.93 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.10 (d, J=2.4Hz, 1H), 8.16-8.20 (m, 2H), 8.28 (d, J=8.8 Hz, 1H); MS (ES+): m/z 354.0(100) [MH⁺]; HPLC: t_(R)=4.2 min (OpenLynx, polar_(—)5 min).

2-Phenylquinolin-7-ol

To a solution of 7-(tert-butyldimethylsilyloxy)quinoline (3.992 g, 15.39mmol) in dry THF (35 mL), cooled by ice/water, was added phenyllithium(1.8 M in cyclohexane:ether 70:30, 10 mL, 18 mmol). The solution slowlywarmed up to ambient temperature and was stirred overnight. Morephenyllithium (1.0 mL, 1.8 mmol) was added, and stirring was continuedfor 4 h. The reaction was quenched by adding saturated NH₄Cl solutionand water. Most of the THF was evaporated, the residue was extractedwith EtOAc (4×30 mL) and the combined EtOAc layers were washed withwater (2×) and brine and dried over MgSO₄. LC/MS indicated that asignificant amount of the TBDMS ether had been cleaved during theworkup, the ratio of quinolines to dihydroquinolines was about 1:1. Airwas bubbled into the solution overnight, the MgSO₄ was filtered off, thefiltrate was concentrated, dissolved in MeOH, aq. HCl (2 M, 2 mL, 4mmol) was added, and the solution was stirred at ambient temperatureovernight. Sat. NaHCO₃ solution was added, most of the MeOH wasevaporated, water (≈100 mL) was added, and the dark brown precipitatewas filtered off and washed with more water. The combined filtrate andwashings were extracted with EtOAc (4×60 mL), the combined EtOAcextracts were washed with water and brine and dried over MgSO₄. The darkbrown precipitate was dissolved in MeOH (≈100 mL), the solution wasfiltered, and the filtrate was adsorbed onto Hydromatrix andchromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge,eluting with CH₂Cl₂→5% EtOAc in CH₂Cl₂→10% EtOAc→15% EtOAc]. The mixedfractions were combined with the crude material from the EtOAc extractsand chromatographed on silica gel [Jones Flashmaster, material adsorbedonto Hydromatrix, 10 g/70 mL cartridge, eluting with CH₂Cl₂→5% EtOAc inCH₂Cl₂→7.5% EtOAc]. Combination of pure fractions of both columns gavethe title compound as light beige solid; ¹H NMR (DMSO-d₆, 400 MHz) δ7.15 (dd, J=8.8, 2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.45-7.51 (m, 1H),7.51-7.57 (m, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),8.20-8.25 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 10.19 (s, 1H); MS (ES+): m/z222.1 (100) [MH⁺]; HPLC: t_(R)=2.2 min (OpenLynx, polar_(—)5 min).

Additionally, 2-phenylquinolin-7-ol can be prepared as follows: Into asuspension of 7-hydroxyquinoline (290.3 mg, 2.0 mmol) in THF (5 mL),which was cooled in ice/H₂O bath, was added PhLi (1.8 M in n-Bu₂O, 2.05eq., 2278 μL) dropwise under N₂ over 5 min. After stirring at 0° C. for1 h, the ice/H₂O bath was removed and the mixture was warmed to rt andstirring was continuing for another 1-3 h. After that time, methanol (10mL) was added followed by addition of H₂O (20 mL). The mixture was thenextracted with EtOAc (4×20 mL). The extracts were washed with brine(4×20 mL). Air was bubbled through the above extracts at rt whilestirring for 3-4 days. After that time, solvent was removed in vacuo andthe solid was triturated with 50% EtOAc/Hexane (20 mL) to obtain thetitle compound as a brown powder.

7-(tert-Butyldimethylsilyloxy)quinoline

To a suspension of 7-hydroxyquinoline (2.240 g, 15.43 mmol) in dryCH₂Cl₂ (30 mL) were added (in this order) DMAP (94 mg, 0.77 mmol),triethylamine (4.3 mL, 3.1 g, 31 mmol), and TBDMSCl (2.558 g, 16.97mmol), and the mixture was stirred overnight at ambient temperature.Water and sat. NH₄Cl sol. (10 mL each) were added, the layers wereseparated, and the aqueous layer was extracted with CH₂Cl₂ (2×30 mL).The combined organic layers were washed with 0.25 M citric acid (2×),water, sat. NaHCO₃ solution, and brine, and dried over MgSO₄. EtOAc (10mL) was added to the solution, which was then filtered through a silicagel plug (60 mL glass frit filled ≈½ with silica gel) and concentratedto give the title compound as pale yellow oil. The material thusobtained was used without further purification; ¹H NMR (CDCl₃, 400 MHz)δ 0.29 (s, 6H), 1.03 (s, 9H), 7.15 (dd, J=2.8, 8.8 Hz, 1H), 7.26 (dd,J=4.0, 8.0 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 8.08(dd, J=0.8, 8.0 Hz, 1H), 8.83 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z260.2 (100) [MH⁺]; HPLC: t_(R)=3.8 min (OpenLynx, polar_(—)5 min).

Additionally,2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline canbe prepared as follows: A mixture of 7-chloro-2-phenylquinoline (14.40g, 60 mmol), bis(pinacolato)diboron (17.1 g, 69.6 mmol), KOAc (14.7 g,150 mmol), Pd(OAc)₂ (400 mg, 1.8 mmol) and1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (1.53 g, 3.6 mmol) inTHF (300 mL) was refluxed under nitrogen overnight (14 h). LC-MS showedthe reaction completed. The mixture was diluted with EtOAc (300 mL) andbrine (100 mL), then filtered through celite to remove most of the blackmaterials. Another two reactions from 60 mmol and 40 mmol of7-chloro-2-phenylquinoline were combined with the above. All thefiltrates were combined, washed with brine (300 mL), and dried overanhydrous sodium sulfate. Filtration through a pad of silica gel removedthe trace amount of black materials. The filtrate was concentrated underreduced pressure to ca. 500 mL, the white precipitate was collected byfiltration to afford the first batch of product. The filtrate wasfurther concentrated to 200 mL and provided the second batch as alight-yellow solid. The filtrate was then concentrated to 100 mL andprovided the third batch of the title compound as a light-yellow solid;LC-MS (ES, Pos.): 332 (MH⁺) and 250 (for the corresponding boronic acidhydrolyzed under LC-MS acid condition); ¹H NMR (CD₃COCD₃, 400 MHz) δ1.41 (s, 12H), 7.48-7.58 (m, 3H), 7.85 (dd, J=8.0, 1.0 Hz, 1H), 7.96 (d,J=8.0 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 8.34-8.36 (m, 2H), 8.42 (d, J=8.6Hz, 1H), 8.55 (s, 1H).

7-Chloro-2-phenyl-quinoline

To a solution of 4-chloro-2-nitrobenzaldehyde (55.7 g, 300 mmol) inethanol (600 mL) and water (60 mL) was added iron powder (167 g, 3000mmol) and conc. HCl (5 mL, 60 mmol), the resulting mixture was stirredwith a mechanical stirrer under refluxing condition. 1 h later, LC-MSshowed ca. 50% conversion, there was not much change after another onehour. Conc. HCl (2 mL) was added, LC-MS showed the reduction wascomplete after the mixture was refluxed for an additional 30 min. Thenacetophenone (35 mL, 300 mmol) and KOH (50.5 g, 900 mmol) were added,the resulting mixture was further refluxed for 1 h, LC-MS showed thereaction was complete and the desired product was formed. The mixturewas cooled to 40° C. and diluted with methylene chloride (1 L), thenfiltered through celite and the filtrate was concentrated. The residuewas dissolved in methylene chloride (1 L) and washed with brine (2×300mL), and dried over anhydrous sodium sulfate. The solvent wasconcentrated to ca. 200 mL and diluted with hexanes (500 mL), thelight-yellow solid was collected by filtration as the first batch ofdesired product. The mother liquid was concentrated and thenrecrystallized with acetonitrile to give the second batch of the titlecompound as a light-yellow solid; LC-MS (ES, Pos.): 240/242 (3/1) [MH⁺];¹H NMR (CDCl₃, 400 MHz) δ 7.46-7.56 (m, 4H), 7.77 (d, J=8.7 Hz, 1H),7.89 (d, J=8.6 Hz, 1H), 8.14-8.18 (m, 3H), 8.20 (d, J=8.6 Hz, 1H).

2-Pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline

N₂ was bubbled into a stirred mixture of7-chloro-2-pyridin-2-ylquinoline (38.225 g, 158.8 mmol), diboron (46.765g, 184.15 mmol), PdCl₂(dppf). CH₂Cl₂ (32.413 g, 39.69 mmol), and KOAc(38.96 g, 396.9 mmol) in THF (700 mL) for 10 min. This mixture was thenstirred under reflux for 72 h. After cooled to rt, EtOAc (300 mL) andwater (200 mL) were added. The organic layer was collected and theaqueous phase was extracted with EtOAc (300 mL). The combined organicphases were dried over MgSO₄, filtered through a Celite pad,concentrated in vacuo to a volume of ˜200 mL. This black-coloredsolution was passed through a short silica column, which was washed withEtOAc (1800 mL). The resulting organic phase was concentrated (˜200 mL)and passed through another short silica column. The above process wasrepeated until the color of the resulting EtOAc solution turned to lightbrown to orange. At this point, almost all the catalyst was removed. TheEtOAc solution was concentrated under reduced pressure to ˜100 mL.Products crashed out were collected by filtration. The above process wasrepeated several times until most of the products were fished out.Combining all batches afforded the title compound as an off-white solidproduct; ¹H-NMR (Acetone-d₆, 400 MHz) δ 1.41 (s, 12 H), 7.47-7.51 (m, 1H), 7.88 (dd, J=1.2, 8.0 Hz, 1 H), 7.99-8.03 (m, 2 H), 8.47 (d, J=8.8Hz, 1 H), 8.57 (s, 1 H), 8.71 (d, J=8.4 Hz, 1 H), 8.74-8.77 (m, 2 H); MS(ES+): m/z 333.2 (Min; HPLC: t_(R)=4.30 min (OpenLynx, polar_(—)5 min).

2-Pyridin-3-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline

Prepared according to the procedures for2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline;MS (ES+): 333.4 (M+1), t_(R)(polar-5 min)=3.7 min.

2-Pyridin-4-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline

N₂ was bubbled into a stirred mixture of7-chloro-2-pyridin-4-ylquinoline (240.7 mg, 1.0 mmol), diboron (294.6mg, 1.16 mmol), Pd(OAc)₂ (6.7 mg, 0.03 mmol), imidazolium ligand (25.5mg, 0.06 mmol) and KOAc (245 mg, 2.5 mmol) in THF (20 mL) for 10 min.This mixture was then refluxed under N₂ overnight. Solvents were removedand the residue was purified by silica gel chromatography (10% EtOAc inhexane) to afford a mixture of the desired title compound and2-pyridin-4-ylquinoline. This mixture was used directly in the nextstep; ¹H-NMR (CDCl₃, 400 MHz) δ 1.41 (s, 12 H), 7.58-7.62 (m, 1 H), 7.84(d, J=8.4 Hz, 1 H), 7.94 (d, J=8.4 Hz, 1 H), 8.07-8.10 (m, 2 H), 8.28(d, J=8.8 Hz, 1 H), 8.71 (s, 1 H), 8.77-8.80 (m, 2 H); MS (ES+): m/z 333[MH⁺].

General Procedure for Preparing Pyridinyl-derived Quinolines:7-Chloro-2-pyridin-2-ylquinoline

Iron powder (167 g, 2990 mmol), water (60 mL), and concentratedhydrochloric acid (3 mL, ˜36 mmol) were added consecutively to asolution of 4-chloro-2-nitrobenzaldehyde (55.7 g, 300 mmol) in EtOH (600mL). After stirred (mechanically) at 95° C. for 10 min, another aliquotof concentrated hydrochloric acid (2 mL, ˜24 mmol) was added. Stirringwas continued at 95° C. for another 80 min. 1-Pyridin-2-ylethanone (33mL, 294.1 mmol) and solid KOH (50.5 g, 900 mmol) were then added inportions with caution. The resulting mixture was stirred at 95° C. for 4h. After cooled to rt, the reaction was diluted with dichloromethane(500 mL) and filtered through a Celite pad. The filtrate wasconcentrated to approximately 100 mL. The desired precipitated productwas collected by filtration; ¹H-NMR (CDCl₃, 400 MHz) δ 7.37-7.40 (m, 1H), 7.51 (dd, J=2.0, 8.8 Hz, 1 H), 7.79 (d, J=8.4 Hz, 1 H), 7.89 (dt,J=1.6, 8.0 Hz, 1 H), 8.19 (s, 1 H), 8.26 (d, J=8.8 Hz, 1 H), 8.57 (d,J=8.8 Hz, 1 H), 8.64 (d, J=8.4 Hz, 1 H), 8.74-8.75 (m, 1 H); MS (ES+):m/z 241 (MH⁺, ³⁵Cl), 243 (M=H⁺, ³⁷Cl); HPLC: t_(R)=3.95 min (OpenLynx,polar_(—)5 min).

7-Chloro-2-pyridin-3-ylquinoline

Prepared according to the general procedure for pyridinyl-derivedquinolines; ¹H-NMR (CDCl₃, 400 MHz) δ 7.47 (dq, J=0.8, 4.8 Hz, 1 H),7.52 (dd, J=2.0, 8.8 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 7.90 (d, J=8.8Hz, 1 H), 8.19 (d, J=2.0 Hz, 1 H), 8.26 (d, J=8.4 Hz, 1 H), 8.50-8.53(m, 1 H), 8.72 (dd, J=1.6, 4.8 Hz, 1 H), 9.35 (dd, J=0.8, 2.4 Hz, 1 H);MS (ES+): m/z 241 (MH⁺, ³⁵Cl), 243 (MH⁺, ³⁷Cl); HPLC: t_(R)=3.35 min(OpenLynx, polar_(—)5 min).

7-Chloro-2-pyridin-4-ylquinoline

Prepared according to the general procedure for pyridinyl-derivedquinolines; ¹H-NMR (CDCl₃, 400 MHz) δ 7.55 (dd, J=2.4, 8.8 Hz, 1 H),7.81 (d, J=8.8 Hz, 1 H), 7.92 (d, J=8.4 Hz, 1 H), 8.05-8.06 (m, 2 H),8.21 (d, J=2.0 Hz, 1 H), 8.28 (d, J=8.4 Hz, 1 H), 8.79-8.81 (m, 2 H); MS(ES+): m/z 241 (MH⁺, ³⁵Cl), 243 (MH⁺, ³⁷Cl); HPLC: t_(R)=3.22 min(OpenLynx, polar_(—)5 min).

4-Chloro-2-nitrobenzaldehyde

A solution of 4-chloro-2-nitrotoluene (514.8 mg, 3.000 mmol) anddimethylformamide dimethylacetal (1.200 ml, 1074 mg, 9.000 mmol) in DMF(1.2 ml) was heated at 135° C. in a sealed tube for 15 h. The reactionmixture was cooled to rt and added dropwise to a 20° C. solution ofNaIO₄ (1926 mg, 9.000 mmol) in water (6.18 ml) and DMF (3.09 ml). After3 h, the mixture was treated with water (20 ml) and extracted with EtOAc(3×15 ml). The extracts were washed with water (3×15 ml) and brine (15ml), and dried over MgSO₄. After the solid was filtered off and thesolvent was removed in vacuo, a brown solid of4-chloro-2-nitrobenzaldehyde was obtained (J. Org. Chem. 2003, 68,4104-4107). NMR (CDCl₃, 400 MHz) δ 7.74-7.78 (m, 1 H), 7.94-7.96 (m, 1H), 8.11-8.12 (m, 1 H), 10.39 (s, 1 H).

4-Methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

A mixture of 7-chloro-4-methyl-2-phenylquinoline (335 mg, 1.3 mmol),bis(pinacolato)diboron (389 mg, 1.5 mmol), Pd(OAc)₂ (18 mg, 0.08 mmol),1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (67 mg, 0.16 mmol)and KOAc (130 mg, 1.3 mmol) in anh THF (18 mL) under Ar heated at refluxfor 21 h. Then the reaction was charged again with Pd(OAc)₂ (18 mg, 0.08mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (67 mg, 0.16mmol) and evacuated and refilled with Ar (4×) while being cooled in adry ice-acetone bath. The reaction mixture was heated at reflux for 27h. The mixture was the cooled to rt, diluted with EtOAc (100 mL), washed(brine, 2×20 mL), dried (Na₂SO₄) and concentrated under reduced pressureto yield a light brown gum. The material was taken into hexanes toprovide the title compound as a yellow solid which was used in thefollowing step without further purification; MS (ES+): m/z 346.2 (100)[MH⁺]; HPLC: t_(R)=3.99 min (OpenLynx, nonpolar_(—)5 min).

7-Chloro-4-methyl-2-phenylquinoline

Acetophenone (0.66 mL, 5.69 mmol) was added to1-(2-amino-4-chlorophenyl)ethanone (0.868 g, 5.69 mmol) and [Hbim]BF₄(1.50 g, 7.08 mmol) under Ar. The reaction mixture was heated at 100° C.for 57 h then cooled to rt and partitioned between EtOAc and H₂O. The aqlayer was extracted with EtOAc. The combined organics were dried(Na₂SO₄) and concentrated under reduced pressure. Purification by flashchromatography on SiO₂ (70 g, EtOAc in hexanes 0:100->1:40->1:30)afforded a lightly colored oil. The material was dissolved in DCM (100mL) and stirred with PS-Ts-NHNH₂ (2.07 g, 2.87 mmol/g, 5.94 mmol) for2.5 d at rt and then with MP-carbonate (˜0.25 g, 2.74 mmol/g, 0.68 mmol)for 4 h. The resins were removed by filtration through Celite. Theresidue and Celite were rinsed with DCM multiple times. The filtrate wasconcentrated under reduced pressure to provide the title compound as alight yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.12 (m, 3H), 7.92 (d,J=8.4 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.54-7.46 (m, 4H), 2.75 (s, 3H);MS (ES+): m/z 254.24 (35) [MH⁺]; HPLC: t_(R)=3.82 min (OpenLynx,nonpolar_(—)5 min).

1-(2-amino-4-chlorophenyl)ethanone

To a vigorously stirred, Et₂O (100 mL) solution of2-amino-4-chloroberizonitrile (1.00 g, 6.55 mmol) cooled in an ice-H₂Obath was added MeMgCl (3.0 M in THF, 6.5 mL, 19.7 mmol) dropwise over 5min. During that time the reaction became a thick yellow suspension.Stirring was continued at the temperature for 1 h before the coolingbath was removed and the reaction stirred for 21 h at rt. The resultantlight yellow suspension cooled to −60° C. and treated with aq HCl (5 M,8 mL, 40 mmol) dropwise over ˜3 min. The mixture was allowed to warmslowly to it within the cooling bath. Later more aq HCl (5 M, 6.5 mL, 33mmol) was added. The Et₂O layer was separated, the aq phase wasbasicified (pH 4-5) by addition of solid KOH and later extracted withEtOAc (3×). The Et₂O and EtOAc layers were combined, dried (Na₂SO₄) andconcentrated under reduced pressure to afford the title material whichwas used without further purification; ¹H NMR (400 MHz, CDCl₃) δ 7.63(d, J=8.4 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.60 (dd, J=2.0 Hz, 8.0 Hz,1H), 6.40 (br, 2H), 2.55 (s, 3H); MS (ES+): m/z 170.07 (100) [MH⁺];HPLC: t_(R)=3.12 min (OpenLynx, polar_(—)5 min).

4-Methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline

A flask containing dry 7-chloro-4-methyl-2-phenylquinazoline under Arwas charged with KOAc (80 mg, 0.81 mmol), bis(pinacolato)diboron (151mg, 0.60 mmol) and Pd[P(C₆H₁₁)₃]₂ (Strem, 22 mg, 0.03 mmol) (thecatalyst was added rapidly minimizing exposure to air). A refluxcondenser was attached and the set-up was quickly evacuated and refilledwith Ar (3×). Anh. 1,4-dioxane was added via syringe (2 mL) and thereaction mixture was stirred at rt for 30 min (brown solution) and laterheated at 80° C. for 3 d. The reaction was evaporated to dryness underhigh vacuum at 35° C., purified by flash chromatography (silica gel,100:0.5-10:1 hexanes:EtOAc) affording the title compound as a lightyellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.70-8.56 (m, 2H), 8.02 (d,J=8.4 Hz, 1H), 7.99 (dd, J=1.2 Hz, 8.0 Hz, 1H), 7.58-7.43 (m, 4H), 2.99(s, 3H), 1.38 (s, 12H).

4-Methoxy-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline

Synthesized from of 7-chloro-4-methoxy-2-phenylquinazoline (189 mg, 0.7mmol) as4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline;off-white solid. MS (ES+): m/z 347.2 (20) MS (ES+): m/z 281.2 (100)[MH⁺-82]; HPLC: t_(R)=3.19 min (OpenLynx, polar_(—)5 min).

4,7-Dichloro-2-phenylquinazoline

7-Chloro-2-phenylquinazolin-4(3H)-one (3.11 g, 12.1 mmol) in POCl₃ (40mL) was heated with stirring at 90° C. under N₂ for 2 d. The reactionwas cooled to rt and evaporated to dryness under high vacuum. Theresidue was stirred for 30 min at 0° C. under Ar as a suspension inNH₃/i-PrOH (2 M, 45 mL). Later DCM (˜100 mL) was added and stirring wascontinued for 1 h at it Aq NH₄OH (conc, 50 mL) was added and layers wereseparated. The aqueous layer was extracted with DCM (2×). The organicphase was washed (satd NaHCO₃, H₂O, brine), dried (Na₂SO₄) andconcentrated under reduced pressure to provide the title compound as alight yellow solid; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.56-8.46 (m, 2H), 8.14(d, J=9.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.56 (dd, J=2.4 Hz, 9.2 Hz,1H), 7.52-7.45 (m, 3H).

7-Chloro-4-methyl-2-phenylquinazoline

MeMgC1 (3.0 M in THF, 0.36 mL, 1.1 mmol) was added dropwise to a redsolution of 4,7-dichloroquinazoline (297 mg, 1.1 mmol) and Fe(acac)₃ (38mg, 0.11 mmol) in THF (10 mL) at rt under Ar. On addition the reactionbecame black. Stirring was continued for 3 h at rt. Satd aq NH₄Cl (5 mL)was added and the reaction was left standing overnight. The aqueouslayer was extracted with DCM (3×). The combined organics were washed(0.13 M aq citric acid (2×), brine), dried (Na₂SO₄) and concentratedunder reduced pressure. The crude material was purified by flashchromatography (SiO₂, 50 g, 0-3% EtOAc in hexanes) affording the titlecompound as a light yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.65-8.56(m, 2H), 8.08 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.58-7.46 (m,4H), 2.98 (s, 3H).

7-Chloro-4-methoxy-2-phenylquinazoline

A flask containing 4,7-dichloroquinazoline (250 mg, 0.91 mmol) equippedwith a reflux condenser was evacuated and refilled with Ar severaltimes. MeONa (2 mL, 25% wt in MeOH, 8.7 mmol) and anh. MeOH (20 mL) wereadded and the reaction mixture was heated to reflux under Ar for 5 h.The reaction was cooled to rt and stored at rt overnight thenpartitioned between DCM (80 mL) and H₂O (10 mL). The aqueous layer wasextracted with DCM (1×). The combined organics were washed (brine),dried (Na₂SO₄) and concentrated under reduced pressure to provide thetitle compound as an off-white solid; ¹H NMR (400 MHz, CDCl₃) δ8.55-8.62 (m, 2H), 8.08 (d, J=9.2 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H),7.52-7.48 (m, 3H), 7.45 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.28 (s, 3H).

2-Phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline

A flask containing 7-chloro-2-phenylquinazoline (76 mg, 0.32 mmol) underAr was charged, minimizing exposure to air, with KOAc (47 mg, 0.47mmol)), bis(pinacolato)diboron (88 mg, 0.35 mmol) and Pd(PCy₃)₂ (13 mg,0.019 mmol). A reflux condenser was attached and the set-up was rapidlyevacuated and refilled with Ar (3×). Anh. 1,4-dioxane was added viasyringe (5 mL) and the reaction mixture was stirred at rt for 30 min andlater heated at 80° C. (bath temperature) for 92 h. The reaction wasthen evaporated to dryness and purified by flash chromatography (silicagel, 10:1 to 10:3 hexanes:EtOAc then 2:1 hexanes:EtOAc) to afford thetitle compound as a light yellow solid; ¹H NMR (400 MHz, CD₂Cl₂) δ 9.49(s, 1H), 8.70-8.60 (m, 2H), 8.51 (s, 1H), 7.94 (s, 2H), 7.60-7.46 (m,3H), 1.40 (s, 12H).

7-Chloro-2-phenylquinazoline

7-Chloro-2-phenylquinazolin-4(3H)-one (40 mg, 0.16 mmol) was suspendedin POCl₃ (2 mL) and heated to 50° C. with stirring for 24 h. Later thereaction was heated to 90° C. for 16 h. With minimum exposure tomoisture, the crude mixture was evaporated to dryness under reducedpressure and treated with 2 M NH₃/i-PrOH (8 mL) with cooling on ice-H₂Obath under Ar. The mixture was partitioned between DCM and H₂O and theorganic layer was washed (H₂O, satd NaHCO₃ and brine), dried (Na₂SO₄) toafford crude material which was used directly in the followingde-chlorination step. The crude material (31 mg, 0.113 mmol) andtosylhydrazide (63 mg, 0.34 mmol) were dissolved in anh CHCl₃ (10 mL)and heated at 60° C. (overnight, bath temperature) and, then refluxedfor 4 h. The solvent was removed under reduced pressure and the solidresidue was heated under Ar in anh. PhMe (10 mL) and anh ClCH₂CH₂Cl (5mL) at 80° C. (bath temperature) for 63 h: The reaction was cooled to rtand a pale yellow precipitate was collected by filtration and washedwith PhMe and DCM (2×). The collected solid in aq Na₂CO₃ (10%, 10 mL)was placed in a preheated bath at 90° C. After stirring at thetemperature for 45 min, the reaction was cooled and left standing at itovernight. The crude reaction mixture was extracted with DCM (3×),washed (H₂O, brine), dried (Na₂SO₄), concentrated under reducedpressure, and purified by flash chromatography (silica gel, 100:0->10:1EtOAc:hexanes) to afford the title compound as a light orange solid; ¹HNMR (400 MHz, CDCl₃) δ 9.43 (s, 1H), 8.63-8.56 (m, 2 H), 8.09 (d, J=0.8Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.58-7.50 (m, 4H).

7-Chloro-2-phenylquinazolin-4(3H)-one

To a suspension of N-(5-chloro-2-cyanophenyl)benzamide (150 mg, 0.58mmol) in H₂O (5 mL) was added in sequence NaOH (100 mg, 2.5 mmol) andH₂O₂ (30% in H₂O, 0.25 mL, 2.2 mmol). The reaction was heated to 80° C.for 24 h then cooled to it and stirred at it for 1d. Aq HCl (2 M, 6 mL)was added forming a thick precipitate that was collected by afiltration. The filter cake was washed with H₂O several times affordingthe title compound as a creamy-white solid; MS (ES+): m/z 257.1 (100)[MH⁺]; HPLC: t_(R)=3.34 min (OpenLynx, polar_(—)5 min).

N-(5-Chloro-2-cyanophenyl)benzamide

To a solution of 2-amino-4-chlorobenzonitrile (7.25 g, 47.5 mmol), inanh. pyridine (38 mL, 475 mmol) and DCM (300 mL) cooled in an ice-H₂Obath under Ar was added PhCOCl (5.8 mL, 50 mmol) dropwise. The reactionwas allowed to slowly warm to rt within the cooling bath and then wasstirred at rt overnight. The reaction mixture was washed (H₂O, 2 M aqHCl (2×), H₂O, brine), dried (Na₂SO₄) and concentrated under reducedpressure to afford the title compound as a white solid; MS (ES+): m/z257.1 (100) [MH⁺]; HPLC: t_(R)=3.27 min (OpenLynx, polar_(—)5 min).

8-Fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline

A stirred solution of 7-chloro-8-fluoro-2-phenylquinoline (923 mg, 3.58mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1060mg, 4.15 mol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenehydrochloride (90 mg, 0.2 mmol), palladium acetate (20 mg, 0.1 mmol) andpotassium acetate (880 mg, 9.0 mmol) in anhydrous tetrahydrofuran (20mL) was heated to reflux under nitrogen overnight. The reaction mixturewas allowed to cool to rt, and was diluted with ethyl acetate (50 ml).The mixture was filtered through celite, washing with ethyl acetate (100ml). The resulting organic layer was washed with brine (2×50 ml), dried(MgSO₄), filtered and concentrated. Trituration using dichloromethaneand hexanes gave the title compound as an off-white solid; ¹H NMR(Acetone-d₆, 400 MHz) δ 8.34 (1H, dd, J=12.1 Hz, 2.6 Hz), 8.23 (2H, d,J=8.9 Hz), 8.12 (1H, d, 8.6 Hz), 7.63 (2H, d, 2.5 Hz), 7.47-7.37 (3H,m), 1.27 (12H, s).

7-Chloro-8-fluoro-2-phenyl-quinoline

To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) andtrans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6NHCl (100 ml). The resulting suspension was heated at reflux for 40hours. After cooling, the reaction mixture was poured into 5N NaOHsolution (200 ml) and extracted with EtOAc (3×100 ml). The combinedorganics were washed with brine (2×100 ml), dried (MgSO₄), filtered andconcentrated. The crude product was dissolved in MeOH and loaded onto anSCX-2 cartridge (50 g/150 ml), and the product eluted with MeOH, givingthe title compound as a yellow solid. Additionally, the title compoundcould be prepared as follows:4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF(240 mL) were combined in a 3 neck 1 L round bottom flask with amagnetic stir bar under an atmosphere of nitrogen. The reaction wasstirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M ofn-butyllithium in Hexane (7.34 mL) was then added dropwise over 3minutes so as not to exceed −90° C. The solution turned light green, anddarkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) wasadded 3 minutes after the n-butyllithium addition was done. The coolingbath was removed, and the reaction was allowed to stir for 20 minutes.To work up, saturated sodium bicarbonate solution (100 mL) was added,and the mixture was transferred to a 1 L separatory funnel with 250 mLof ethyl acetate. The layers were separated, and the organic layer waswashed with 2×60 mL of brine. The organic solution was suction filteredthrough a short pad of silica gel, rinsing with ethyl acetate. Thefiltrate was concentrated in vacuo, and the residue was placed underhigh vacuum overnight to afford the crude product. The crude product waspre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL ofToluene was added, and the slurry was concentrated on the rotovap toafford a finely divided powder. This was applied to a silica column andchromatographed (4:3 hexanes/methylene chloride) affording the titlecompound as a white solid. The solid was re-chromatographed with, andthen placed in the vacuum oven at 45° C. overnight to afford the verypure product as a white solid; ¹H NMR (CDCl₃, 400 MHz) δ 8.24-8.21 (3H,m), 7.96 (1H, d, J=8.6 Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13[MH^(+]; HPLC: t) _(R)=3.64 min (MicromassZQ, non-polar_(—)5 min).

8-Fluoro-4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline

7-Chloro-8-fluoro-4-methyl-2-phenylquinoline (390 mg, 1.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (423 mg, 1.66mmol), potassium acetate (352 mg, 3.59 mol), palladium acetate (9.7 mg,0.043 mol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenehydrochloride (37 mg, 0.086 mol), and THF (2.9 mL) were combined in a 25mL R.B. flask fit with a reflux condenser. The reaction was stirred andsubject to 3 vacuum—argon cycles, and then refluxed for 2 days. Thereaction was allowed to cool, and was then filtered through a pad ofsilica gel eluting rinsing with THF. The solvent was evaporated invacuo, and the residue was stirred in 15 mL of hexanes. The solid wascollected, washed with hexanes and put under vacuum overnight to affordthe title compound as a white crystalline solid; ¹H NMR (CDCl₃, 400 MHz)δ 1.37 (s, 12H), 2.77 (s, 3H), 7.52-7.60 (m, 3 H), 7.70-7.73 (dd, 1 H,J=8.3 & 5.6 Hz), 7.87-7.89 (dd, 1 H, J=8.3 Hz), 8.18 (d, 1H, J=0.8 Hz),8.27-8.30 (m, 2H); MS (ES+): 349.93 (100) [MH+]; HPLC t_(R)=3.94 min(OpenLynx, nonpolar_(—)5 min).

7-Chloro-8-fluoro-4-methyl-2-phenylquinoline

4-Bromo-7-chloro-8-fluoro-2-phenylquinoline (1.1 g, 03.3 mmol), methaneboronic acid (196 mg, 3.27 mmol), potassium carbonate (1.4 g, 9.8 mmol)and 1,4-dioxane (4 mL) were combined and stirred in a 10 mL R.B. flask.The flask was subjected to 3 vacuum-argon cycles.Tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol) was added,and the reaction was again subjected to 3 vacuum argon-cycles. Thereaction was heated at 108° C. (external temperature) for 27 h, at whichpoint the reaction was allowed to cool, and was diluted with ethylacetate (30 mL), and water (30 mL). The layers were separated, and theaqueous layer extracted with ethyl acetate (30 mL). The organics werecombined, dried over sodium carbonate, and concentrated in vacuo. Theresidue was chromatographed on silica gel, eluting withhexanes:methylene chloride 2:1. This afforded the title compound as awhite solid; ¹H NMR (CDCl₃, 400 MHz) δ 2.75 (s, 3H), 7.47-7.55 (m, 4H),7.69-7.72 (dd, 1H, J=8.9 & 1.6 Hz), 7.77 (s, 1H), 8.18-8.21 (m, 2H); MS(APCI+): 272.07 (100) [MH+], 274.03 (30) [(M+2)H+F]; HPLC t_(R)=3.80 min(OpenLynx, nonpolar_(—)5 min).

4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline

Phosphorus oxybromide (19 g, 0.066 mole),7-chloro-8-fluoro-2-phenyl-1H-quinolin-4-one (6.2 g, 0.022 mole) andacetonitrile (40 mL) were combined in a 150 mL pressure bottle with amagnetic stir bar. The flask was heated at 100° C. and stirredovernight. Heat was removed, and an ice-water bath was installed. After10 minutes, the bottle was opened, and water (60 mL) was added to thecooled stirring reaction. The quenching was exothermic to ca. 50° C.After stirring 10 minutes, a nice, filterable solid had formed, however,the reaction was extracted with 100 mL, then 3×50 mL methylene chloride.The extracts were combined, washed with saturated sodium bicarbonatesolution (100 mL), and suction filtered through a small pad of silicagel, rinsing with methylene chloride. The filtrate was concentrated invacuo, and put under high vacuum at 45° C. for 1 h to afford the crudeproduct, which was recrystallized from 100 mL of ethanol, suctionfiltered to collect, and washed with ethanol. The purified product wasvacuum oven dried for 1 h at 45° C. to afford the title compound as awhite solid. A second crop was taken. The mother liquor was concentratedthen chromatographed on silica gel with hexanes/methylene chloride 1:1and combined with the second crop to afford additional material; ¹H NMR(CDCl₃, 400 MHz) δ 7.49-7.55 (m, 4H), 7.87-7.90 (dd, 1H, J=1.7 Hz &J=8.9 Hz), 8.15-8.18 (dd, 2H, J=1.5 Hz & J=7.9 Hz), 8.21 (s, 1H); HPLCt_(R)=4.15 min (OpenLynx, nonpolar_(—)5 min).

7-Chloro-8-fluoro-2-phenyl-1H-quinolin-4-one

3-(3-Chloro-2-fluoro-phenylamino)-3-phenyl-acrylic acid ethyl ester (9.2g, 0.029 mole) and polyphosphoric acid (160 mL, 3.0 mole) were combinedand mechanically stirred under nitrogen at 175° C. external temperaturefor 40 minutes. While still hot, the reaction was poured over 800 mL ofstirring ice-water rinsing with water. The mixture was a finesuspension, and was allowed to stir overnight. After stirring overnight,the mixture was filtered to collect the solid. The solid was washed with4×150 mL water, and then with 4×150 mL of 4:1 ether/methanol. The solidwas placed in the vacuum oven at 45° C. for 4 h and afforded the titlecompound as an off white product; ¹H NMR (DMSO-d₆, 400 MHz) δ 6.58 (bs,1H), 7.50-7.54 (d of d, 1H, J=6.6 Hz & J=8.9 Hz), 7.60-7.64 (m, 3H),7.82-7.84 (m, 2 H), 8.07-8.09 (d of d, 1H, J=1.5 Hz & J=8.7 Hz); MS(ES+): 274.03 (100) [MH⁺], 275.99 (30) [(M+2)H+]. LCMS t_(R)=2.97 min(OpenLynx, polar_(—)5 min).

3-(3-Chloro-2-fluoro-phenylamino)-3-phenyl-acrylic acid ethyl ester

2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate(13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole)were combined in a 250 mL round bottom flask with toluene (60 mL) and amagnetic stir-bar. The reaction was stirred at reflux with a Dean-Starkwater trap. Reflux was stopped after 3 h. The product mixture wasallowed to cool, and was then passed through a short pad of silica gelwith methylene chloride, and concentrated in vacuo. Standing under highvacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanesovernight, then suction filtered to remove a solid impurity. Thefiltrate was concentrated, and put on high vacuum to afford an oil. Theoil was chromatographed with hexanes, ethyl acetate (8:1), and put underhigh vacuum for 1 h to afford the title compound as a yellow oil; ¹H NMR(CDCl₃, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 &J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5 H), 10.21(bs, 1H); MS (ES+): 319.99 (100) [MH⁺], 322.02 (30) [(M+2)H+].

2-Phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline

7-Chloro-2-phenyl-4-trifluoromethyl-quinoline (1.0 g, 0.0033 mole),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.96 g,0.0038 mole), potassium acetate (0.78 g, 0.0081 mole), palladium acetate(0.022 g, 0.0001 mole), and1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride (0.083 g,0.0002 mol) were combined in THF (50 mL). The reaction was stirred andpurged with argon for 5 minutes. The reaction was then stirred at refluxunder an atmosphere of argon overnight. The reaction was allowed tocool, and was then suction filtered through a pad of silica gel. Thefiltrate was concentrated in vacuo and taken up in hexanes. A flocculentdark precipitate formed, and was filtered off. The filtrate wasconcentrated in vacou to afford a brown oil. The oil was chromatographedon Silica gel with Hexanes, THF (60:1), then flushed with THF to affordthe title compound as a tan oil; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.38 (s,12H), 7.58-7.64 (m, 3 H), 7.97-8.00 (dd, 1 H, J=2.1 & 8.5 Hz), 8.10-8.13(dq, 1 H, J=2.1 & J=8.5 Hz), 8.38-8.40 (dd, 2 H, J=2.1 & 8.1 Hz),8.52-8.54 (d, 1 H, J=7.0 Hz); MS (ES+): 400.0 (100) [MH⁺].

7-Chloro-2-phenyl-4-trifluoromethyl-quinoline

4-(3-Chloro-phenylamino)-1,1,1-trifluoro-4-phenyl-but-3-en-2-one (2.8 g,0.0086 mole) and polyphosphoric acid (60 mL) in a 250 mL 3 neck roundbottom flask was stirred mechanically under an atmosphere of Nitrogen at165° C. internal temperature for 3 h. The reaction was poured overstirring ice water (600 ml). The product precipitated, and was collectedby suction filtration, washed with water, and air dried overnight. Thesolids remaining in the Buchner funnel, and beaker from aqueous quenchwere rinsed into a flask concentrated in vacuo, then combined with thefiltered sample and chromatographed on silica gel with 3:1Hexanes/methylene chloride to afford the title compound as a whitesolid; ¹H NMR (CDCl₃, 400 MHz) δ 7.53-7.59 (m, 3 H), 7.60-7.63 (dd, 1 H,J=2.2 & J=9.1 Hz), 8.06-8.09 (dq, 1 H, J=1.9 & J=9.0 Hz), 8.16-8.20 (m,3 H), 8.29 (d, 1H, J=2.1 Hz); ¹⁹F NMR 5-61.48; MS (ES+): 308.0 (100)[MH⁺], 310.0 (30) [M+2H+].

4-(3-Chloro-phenylamino)-1,1,1-trifluoro-4-phenyl-but-3-en-2-one

Into a 1-Neck round-bottom flask was added1,1,1-trifluoro-4-phenyl-but-3-yn-2-one (2.0 g, 0.01 mole), methanol (5mL) and m-chloroaniline (0.961 mL, 0.0091 mol). The reaction wasstirred. TLC (SiO₂, hexanes/methylene chloride 1:1) indicated nearreaction completion after 1 h. After 1.5 h the product was concentratedin vacuo to afford an orange oil, which was placed on high vacuumovernight, affording a yellow gum. The crude product was chromatographedon Silica gel with hexanes, Methylene Chloride 2:1, and place on highvacuum for 2 h to afford the title compound as a yellow gum; ¹H NMR(CDCl₃, 400 MHz) δ 5.74 (s, 1 H), 6.67-6.69 (m, 1 H), 6.85 (m, 1 H),7.08-7.10 (m, 1 H), 7.31-7.39 (m, 4 H), 7.43-7.47 (ft, 1 H), 12.39 (bs,1 H).

1,1,1-Trifluoro-4-phenyl-but-3-yn-2-one

Phenylacetylene (10.8 mL, 0.098 mole) was added into a 3-Neck roundbottom flask under an atmosphere of Nitrogen. THF (100 mL) was added andthe reaction was stirred and cooled to 0° C. 2.5 M n-butyllithium inhexane (36 mL, 0.089 mole) was added via syringe at 0° C. over 30 min.The reaction was stirred at 0° C. for 30 minutes. Ethyl trifluoroacetate(5.31 mL, 0.045 mole) was added via syringe at −60 to −50° C. over 10minutes. The reaction was stirred at −70° C. for 1 h. Ammonium chloride28% w/w in water (60 mL) was added and the mixture was extracted withEther (2×50 mL). The organic phase was dried over magnesium sulfate,filtered and concentrated in vacuo, and then allowed to stand under highvacuum for 2 h to afford an orange oil. The oil was chromatographed onsilica gel with 2:1 hexanes, methylene chloride to afford the titlecompound as a yellow oil; ¹H NMR (CDCl₃, 400 MHz) δ 7.44-7.48 (tt, 2 H),7.55-7.60 (tt, 1 H), 7.67-7.70 (m, 2 H); ¹⁹F NMR (CDCl₃, 400 MHz) δ77.54 (s).

1-Bromo-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine

A suspension of 1-bromo-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (341mg, 1.2 mmol) in IPA (3 mL) was saturated with NH₃(g) at 0° C. for 3min. The tube was sealed and heated at 100° C. for 17 h. H₂O (10 mL) wasadded and the mixture was extracted with EtOAc (3×30 mL). The organicphase was washed with brine and concentrated under reduced pressure toprovide the title compound as a white solid; ¹H NMR (400 MHz, CDCl₃) δ7.30 (d, J=4.8 Hz, 1H), 6.97 (d, J=5.2 Hz, 1H), 5.65 (br, 2H), 3.70(qud, J=0.8 Hz, 8.4 Hz, 1H), 2.55-2.35 (m, 4H), 2.18-1.93 (m, 2H); MS(ES+): m/z 267.1 (100), 269.1 (100) [MH⁺]; HPLC: t_(R)=1.70 min(OpenLynx, polar_(—)5 min).

3-Cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine

A Parr bomb containing8-chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine (759 mg, 2.3 mmol) inIPA (100 mL) was saturated with NH₃(g) for 5 min at 0° C. then sealedand heated at 115° C. for 38 h. The reaction mixture was thenconcentrated under reduced pressure, partitioned between DCM (200 mL)and H₂O (50 mL) and extracted with DCM (50 mL). Combined organicfractions were washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure to provide the title compound as a white solid; ¹H NMR(400 MHz, CDCl₃) δ 7.13 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.63(br, 2H), 3.73 (quintet d, J=0.8 Hz, 8.4 Hz, 1H), 2.60-2.38 (m, 4H),2.20-1.90 (m, 2H); MS (ES+): m/z 315.9 (100) [MH⁺]; HPLC: t_(R)=1.75 min(OpenLynx, polar_(—)5 min).

1-Bromo-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine

To a clear, vigorously stirred and cooled (0° C.) solution of8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (0.75 g, 3.6 mmol) in DCM(90 mL) was added Br₂ (0.28 mL, 5.4 mmol) in DCM (90 mL) over 34 min.The reaction became a light orange suspension towards the end of theaddition. Stirring was continued at the temperature for 10 min thenconcentrated under reduced pressure at rt. The mixture was diluted withH₂O (˜20 mL), basified with 2 M aq NaOH to ˜pH 7-9 and extracted withDCM (3×80 mL). The organic layers were washed (satd aq NaHCO₃, brine),dried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification by flash chromatography on silica gel (50 g cartridge, 100%DCM) yielded the title compound as an off-white solid; ¹H NMR (400 MHz,CD₂Cl₂) δ 7.41 (d, J=5.2 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 3.70 (qud,J=1.2 Hz, 8.4 Hz, 1H), 2.48-2.33 (m, 4H), 2.13-2.02 (m, 1H), 1.98-1.88(m, 1H); MS (ES+): m/z 286.1 (90), 288.0 (100) [MH⁺]; HPLC: t_(R)=3.33min (OpenLynx, polar_(—)5 min).

8-Chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine

8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and MS(1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Arfor 6 h. The reaction was diluted with DCM (˜400 mL), washed (H₂O,brine), dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the crude material by flash chromatography on silica gel(50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the titlecompound as a pale yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d,J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintet d, J=1.2 Hz, 8.4Hz, 1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100)[MH⁺]; HPLC: t_(R)=3.38 min (OpenLynx, polar_(—)5 min).

8-Chloro-3-cyclobutyl-imidazo[1,5-a]pyrazine

Prepared according to the procedures described(8-Chloro-3-(3-methylene-cyclobutyl)-imidazo[1,5a]pyrazine).

Cyclobutanecarboxylic acid (3-chloro-pyrazin-2-ylmethyl)-amide

Prepared according to the procedures described for3-methylene-cyclobutanecarboxylic acid(3-chloropyrazin-2-ylmethyl)-amide.

[3-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol

To a Parr reactor was addedcis-3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate (1.00 g, 1.95 mmol) and i-PrOH (30 mL). Ammonia gas wasbubbled into this mixture for 5 min at −78° C. The reactor was sealedand heated at 110° C. for 60 h with stirring. After cooling to −78° C.,the reactor was opened (after being depressurized) and the reactionmixture was transferred into a flask. The i-PrOH was removed and theresidue was dissolved in 40 mL (1:1) mixture of 4 N HCl (aq) and EtOAcunder heating. Layers were separated and the aqueous phase was basifiedcautiously with solid KOH to pH=>11 at 0° C. The crystals formed duringbasification were collected through filtration, washed with water (3mL×3), dried to afford the desired compound; ¹H-NMR (DMSO-d₆, 400 MHz) δ2.02-2.09 (m, 2 H), 2.34-2.46 (m, 3 H), 3.31-3.37 (m, 2 H), 3.64-3.73(m, 1 H), 4.52 (t, J=5.2 Hz, 1 H), 6.53 (s, br, 2 H), 6.95 (d, J=5.2 Hz,1 H), 7.49 (d, J=5.6 Hz, 1 H); MS (ES+): m/z 344.96; HPLC: t_(R)=1.52min (OpenLynx, polar_(—)5 min).

cis-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate andtrans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate were prepared as follows: To a solution of[3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (˜5:1 mixtureof cis- and trans-isomers, contaminated with unknown amount ofcyclooctane-1,5-diol from the previous reaction, 118.8 mg, 0.5 mmol) andp-toluenesulfonic anhydride (244.8 mg, 0.75 mmol) in dichloromethane(2.0 mL) was added i-Pr₂NEt (0.26 mL, 1.5 mmol). The resulting mixturewas stirred at rt for 15 h. Solvents were removed and the residue waspurified by silica gel chromatography (hexanes/EtOAc: 4/1 to 1/1) toafford the respective cis- and trans-title compounds:

cis-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate

¹H-NMR (CDCl₃, 400 MHz) δ 2.25-2.34 (m, 2 H), 2.45 (s, 3 H), 2.56-2.63(m, 2 H), 2.77-2.86 (m, 1 H), 3.66-3.75 (m, 1 H), 4.06 (d, J=6.4 Hz, 2H), 7.30 (d, J=4.8 Hz, 1 H), 7.34 (d, J=8.8 Hz, 2 H), 7.52 (dd, J=0.8,5.2 Hz, 1 H), 7.76 (s, 1 H), 7.77 (d, J=8.8 Hz, 2 H). MS (ES+): m/z392.06 (MH⁺, ³⁵Cl), 394.01 (MH⁺, ³⁷Cl). HPLC: t_(R)=3.32 min (OpenLynx,polar_(—)5 min).

trans-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate

¹H-NMR (CDCl₃, 400 MHz) δ 2.36-2.43 (m, 2 H), 2.47 (s, 3 H), 2.62-2.69(m, 2 H), 2.79-2.87 (m, 1 H), 3.77-3.83 (m, 1 H), 4.18 (d, J=5.6 Hz, 2H), 7.32 (d, J=5.2 Hz, 1 H), 7.37 (d, J=8.0 Hz, 2 H), 7.45 (d, J=5.2 Hz,1 H), 7.81 (s, 1 H), 7.83 (d, J=8.0 Hz, 2 H). MS (ES+): m/z 392.06 (MH⁺,³⁵Cl), 394.01 (MH⁺, ³⁷Cl). HPLC: t_(R)=3.38 min (OpenLynx, polar_(—)5min).

cis-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate andtrans-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate were prepared according to the general procedure for thepreparation forcis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate andtrans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate, except 4-nitrobenzoyl chloride was used instead ofp-toluenesulfonic anhydride.

cis-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate

¹H-NMR (CDCl₃, 400 MHz) δ 2.51-2.59 (m, 2 H), 2.68-2.75 (m, 2 H),2.92-3.02 (m, 1 H), 3.73-3.82 (m, 1 H), 4.43 (d, J=6.0 Hz, 2 H), 7.32(dd, J=0.8, 5.2 Hz, 1 H), 7.52 (d, J=4.8 Hz, 1 H), 7.83 (s, 1 H), 8.24(d, J=8.8 Hz, 2 H), 8.29 (d, J=8.8 Hz, 2 H). MS (ES+): m/z 387.00 (MH⁺,³⁵Cl), 389.02 (MH⁺, ³⁷Cl). HPLC: t_(R)=3.42 min (OpenLynx, polar_(—)5min).

trans-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate

¹H-NMR (CDCl₃, 400 MHz) δ 2.46-2.53 (m, 2H), 2.74-2.81 (m, 2 H),3.02-3.12 (m, 1 H), 3.88-3.93 (m, 1 H), 4.56 (d, J=7.2 Hz, 2 H), 7.33(d, J=5.2 Hz, 1 H), 7.48 (dd, J=0.8, 5.2 Hz, 1 H), 7.85 (d, J=0.8 Hz, 1H), 8.24 (d, J=9.2 Hz, 2 H), 8.28 (d, J=9.2 Hz, 2 H); MS (ES+): m/z387.00 (MH⁺, ³⁵Cl), 389.02 (MH⁺, ³⁷Cl); HPLC: t_(R)=3.45 min (OpenLynx,polar_(—)5 min).

cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazineandtrans-3-[3-(tert-butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazinewere prepared according to the general procedure for the preparation forcis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate andtrans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate, except tert-butylchlorodimethylsilane was usedinstead of p-toluenesulfonic anhydride.

cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine

¹H-NMR (CDCl₃, 400 MHz) δ 0.05 (s, 6 H), 0.88 (s, 9 H), 2.30-2.39 (m, 2H), 2.49-2.57 (m, 2 H), 2.61-2.67 (m, 1 H), 3.63 (d, J=5.6 Hz, 2 H),3.67-3.72 (m, 1 H), 7.29 (d, J=4.8 Hz, 1 H), 7.60 (dd, J=0.8, 4.8 Hz, 1H), 7.79 (d, J=1.2 Hz, 1 H). MS (ES+): m/z 352.14 (MH⁺, ³⁵Cl), 354.12(MH⁺, ³⁷Cl). HPLC: t_(R)=4.34 min (OpenLynx, polar_(—)5 min).

trans-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine

¹H-NMR (CDCl₃, 400 MHz) δ 0.09 (s, 6 H), 0.94 (s, 9 H), 2.17-2.43 (m, 2H), 2.59-2.71 (m, 3 H), 3.75 (d, J=4.8 Hz, 2 H), 3.80-3.86 (m, 1 H),7.29 (d, J=5.2 Hz, 1 H), 7.45 (dd, J=1.2, 5.2 Hz, 1 H), 7.82 (d, J=0.8Hz, 1 H). MS (ES+): m/z 352.14 (MH⁺, ³⁵Cl), 354.12 (MH⁺, ³⁷Cl). HPLC:t_(R)=4.41 min (OpenLynx, polar_(—)5 min).

cis-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl(R)-formyloxyphenylacetate andtrans-3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl(R)-formyloxyphenylacetate: To a solution of[3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (˜5:1mixture of cis- and trans-isomers, 109.1 mg, 0.3 mmol) and(R)-—O-formylmandeloyl chloride (71.5 mg, 0.36 mmol) in dichloromethane(1.0 mL) was added i-Pr₂NEt (0.16 mL, 0.9 mmol). The resulting mixturewas stirred at rt for 15 h. Solvents were removed and the residue waspurified by silica gel chromatography (hexanes/EtOAc:4/1 to 1/1) toafford the respective cis- and trans-title compounds.

cis-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl(R)-formyloxyphenylacetate

¹H-NMR (CDCl₃, 400 MHz) δ 2.18-2.26 (m, 1 H), 2.31-2.38 (m, 1 H),2.40-2.53 (m, 2 H), 2.67-2.76 (m, 1 H), 3.53-3.60 (m, 1 H), 4.18 (dd,J=4.0, 6.4 Hz, 2 H), 6.04 (s, 1 H), 7.28 (d, J=4.8 Hz, 1 H), 7.33-7.38(m, 3 H), 7.44-7.49 (m, 2 H), 7.46 (d, J=4.8 Hz, 1 H), 8.20 (s, 1 H). MS(ES+): m/z 525.84 (MH⁺, ³⁵Cl), 527.87 (MH⁺, ³⁷Cl). HPLC: t_(R)=3.58 min(OpenLynx, polar_(—)5 min).

trans-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl(R)-formyloxyphenylacetate

¹H-NMR (CDCl₃, 400 MHz) δ 2.18-2.28 (m, 2 H), 2.56-2.67 (m, 2 H),2.67-2.81 (m, 1 H), 3.58-3.64 (m, 1 H), 4.33 (dq, J=5.2, 10.8 Hz, 2 H),6.09 (s, 1 H), 7.28 (d, J=5.2 Hz, 1 H), 7.39-7.45 (m, 4 H), 7.50-7.53(m, 2 H), 8.23 (s, 1 H); MS (ES+): m/z 525.84 (MH⁺, ³⁵Cl), 527.87 (MH⁺,³⁷Cl); HPLC: t_(R)=3.69 min (OpenLynx, polar_(—)5 min).

cis-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate andtrans-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate were prepared according to the general procedure for thepreparation forcis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate andtrans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate, except 4-nitrobenzoyl chloride was used instead ofp-toluenesulfonic anhydride.

cis-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate

¹H-NMR (CDCl₃, 400 MHz) δ 2.56-2.70 (m, 4 H), 2.92-2.99 (m, 1 H),3.67-3.74 (m, 1 H), 4.40 (d, J=5.2 Hz, 2 H), 7.31 (d, J=4.4 Hz, 1 H),7.55 (d, J=5.2 Hz, 1 H), 8.28 (d, J=8.8 Hz, 2 H), 8.36 (d, J=8.8 Hz, 2H); MS (ES+): m/z 512.85 (MH⁺, ³⁵Cl), 514.84 (MH⁺, ³⁷Cl); HPLC:t_(R)=3.81 min (OpenLynx, polar_(—)5 min).

trans-3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl4-nitrobenzoate

¹H-NMR (CDCl₃, 400 MHz) δ 2.43-2.50 (m, 2 H), 2.74-2.81 (m, 2H),3.00-3.08 (m, 1 H), 3.81-3.88 (m, 1 H), 4.54 (d, J=6.8 Hz, 2 H), 7.31(d, J=4.8 Hz, 1 H), 7.50 (d, J=5.2 Hz, 1 H), 8.23 (d, J=8.8 Hz, 2 H),8.31 (d, J=9.2 Hz, 2 H); MS (ES+): m/z 512.84 (MH⁺, ³⁵Cl), 514.85 (MH⁺,³⁷Cl); HPLC: t_(R)=3.84 min (OpenLynx, polar_(—)5 min).

cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloro-1-iodoimidazo[1,5-a]pyrazineandtrans-3-[3-(tert-butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloro-1-iodoimidazo[1,5-a]pyrazinewere prepared according to the general procedure for the preparation forcis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate andtrans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyltoluene-4-sulfonate, except tert-butylchlorodimethylsilane was usedinstead of p-toluenesulfonic anhydride.

cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloro-1-iodoimidazo[1,5-a]pyrazine

¹H-NMR (CDCl₃, 400 MHz) δ 0.05 (s, 6 H), 0.88 (s, 9 H), 2.31-2.38 (m, 2H), 2.46-2.53 (m, 2 H), 2.59-2.65 (m, 1 H), 3.61 (d, J=5.2 Hz, 2 H),3.60-3.66 (m, 1 H), 7.27 (d, J=4.8 Hz, 1 H), 7.62 (dd, J=0.8, 4.8 Hz, 1H). MS (ES+): m/z 477.96 (MH⁺, ³⁵Cl). HPLC: t_(R)=4.21 min (OpenLynx,polar_(—)5 min).

trans-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloro-1-iodoimidazo[1,5-a]pyrazine

¹H-NMR (CDCl₃, 400 MHz) δ 0.09 (s, 6 H), 0.94 (s, 9 H), 2.36-2.40 (m, 2H), 2.58-2.63 (m, 3 H), 3.73 (d, J=4.4 Hz, 2 H), 3.72-3.78 (m, 1 H),7.27 (d, J=0.8, 4.8 Hz, 1 H), 7.47 (dd, J=0.8, 5.2 Hz, 1 H); MS (ES+):m/z 477.93 (MH⁺, ³⁵Cl), 479.96 (MH⁺, ³⁷CO; HPLC: t_(R)=3.77 min(OpenLynx, polar_(—)5 min).

[3-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]methanol

[3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (6.9g) in i-PrOH (200 mL) was saturated with NH_(3(g)), by passing a slow aslow stream of ammonia for 10 min at −20° C., and then heated in a Parrbomb at 110° C. for 2 d. The reaction mixture was then cooled to it,filtered through a sintered glass and the solid residue and the Parrvessel were rinsed with i-PrOH several times. The filtrate wasconcentrated under reduced pressure to provide an orange solid (7.9 g)still containing NH₄Cl. The material was taken up into refluxing MeCN(250 mL) and filtered hot. The step was repeated with another portion ofhot MeCN (200 mL). The combined MeCN filtrates were concentrated underreduced pressure to provide the title compound as an orange solid; HPLC:(polar5 min) 0.53 and 1.51 min; MS (ES+): 345.1 (100, M⁺+1); ¹H NMR (400MHz, DMSO-d6) δ 7.50 (d, J=5.2 Hz, 1 H), 7.44 (d, J=5.2 Hz, 0.27H, minorisomer), 6.95 (d, J=5.2 Hz, 1.29H overlapped with the minor isomer) 6.63(br, 2H), 4.61 (t, J=5.2 Hz, 0.27H, minor isomer), 4.52 (t, J=5.2 Hz,1H), 3.69 (quintet, J=5.6 Hz, 0.32H, minor isomer), 3.54 (quintet, J=5.6Hz, 1H), 2.52-2.25 (m, 4H), 2.10-2.00 (m, 1H).

[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-methanol

To a solution of NIS (6.31 g, 28.0 mmol) in anh DMF (100 mL) under Arwas added dry [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol(6.67 g) dissolved in anh DMF (30 mL). The flask containing[3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol was rinsedwith another portion of anh DMF (20 mL) and the rinse was added to thereaction mixture. The reaction was heated to 60° C. (rt→60° C.˜30 min)and the stirred at this temperature for 3 h. The mixture was then cooledto rt, partitioned between 1 M aq Na₂S₂O₃ (60 mL), brine (60 mL) and DCM(160 mL). The aq layer was extracted with DCM (3×100 mL). The combinedorganics were dried (Na₂SO₄), concentrated under reduced pressure andpurified by flash chromatography on SiO₂ (0-8% MeOH in DCM) to provide amaterial, homogenous by UV on both TLC and HPLC, still containing DMF.The material was dissolved in DCM (200 mL) and washed with water (3×40mL), dried (Na₂SO₄) and concentrated under reduced pressure to providethe title compound as a pale yellow solid; HPLC (polar_(—)5 min) 2.52min; MS (ES+): m/z (rel. int.) 364.0 (100, M⁴+1); ¹H NMR (400 MHz,CDCl₃) δ 7.59 (d, J=4.8 Hz, 1 H), 7.49 (d, J=4.8 Hz, 0.22 H, minorisomer), 7.29 (d, J=4.8 Hz, 1 H), 7.28 (d, J=5.2 Hz, 0.23 H, minorisomer), 3.83-3.80 (m, 0.7 H), 3.72-3.62 (m, 3 H), 2.75-2.55 (m, 4 H),2.42-2.32 (m, 1-2H).

[3-(8-Chloro-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-methanol

To a solution of8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (4.48 g, 20.4mmol) in anh THF (255 mL) at −78° C. under Ar, 9-BBN (61.2 mL, 0.5 M inTHF, 30.6 mmol) was added dropwise over 8 min (a suspension). Thecooling bath was replaced with ice-H₂O and the reaction was allowed towarm slowly to rt. After being stirred for 17 h, H₂O (100 mL,) was addedfollowed by, after ˜5 min, NaBO₃—H₂O (12.2 g, 122.3 mmol) added in onelot. The reaction was stirred at rt for 5 h and then filtered throughCelite. The Celite and residual solids were washed with DCM and EtOAc.The filtrate was concentrated under reduced pressure to yield an aqsolution, which was saturated with NaCl and extracted with EtOAc (3×).The extracts were dried (Na₂SO₄) and concentrated under reduced pressureto yield a light yellow oil which was purified by flash chromatographyon SiO₂ (9:1 DCM:MeOH) to afford the title compound as a light yellowoil; HPLC: t_(R) (mass-directed HPLC, polar 7 min) 2.52 min; MS (ES+):238.0. The addition may be carried out at 0° C. Suspension quicklyclears up after the exchange of cooling baths. The final productcontained 1,5-cis-octanediol derived from 9-BBN. Based on ¹H NMRestimated roughly to be 66% target material and 33% of the byproduct.The crude product was taken onto next step crude, stereoselectivity ofthe product was 4-5:1 as judged by ¹H NMR.

8-Chloro-3-(3-methylene-cyclobutyl)-imidazo[1,5a]pyrazine

3-Methylene-cyclobutanecarboxylic acid(3-chloro-pyrazin-2-ylmethyl)-amide (52.1 g, 219.2 mmol) was dissolvedin 1.0 L of anhydrous MeCN. Followed by the addition of DMF (1.0 mL) andPOCl₃ (100 mL, 1.09 mol). The reaction was heated to 55° C. for 30 min.with a slow N₂ bubbling the reaction. The reaction was then concentratedin vacuo, basified with cold 2.0 M NH₃ in IPA with CH₂Cl₂. TheIPA/CH₂Cl₂ was concentrated in vacuo and the salts were dissolved withminimal water and extracted with CH₂Cl₂ (4×). The organic layers wherecombined and washed with sat. NaHCO₃ (1×), dried over sodium sulfate,filtered and concentrated in vacuo. The crude product was purified viasilica gel column chromatography [eluting with 2:1 Hex:EtOAc] to yieldthe title compound as a light yellow solid; ¹H NMR (400 MHz, CDCl₃) δ3.24-3.30 (4 H, m), 3.78-3.85 (1 H, m), 4.89-4.94 (2 H, m), 7.33 (1 H,d, J=4.99 Hz), 7.53 (1 H, d, J=5.09 Hz), 7.82 (1 H, s); MS (ES+): m/z220.28/222.30 (100/80) [MH⁺]; HPLC: t_(R)=2.87 min (OpenLynx, polar_(—)5min).

3-Methylene-cyclobutanecarboxylic acid(3-chloropyrazin-2-ylmethyl)-amide

C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol),N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol,1.4 eq.), 4-dimethylaminopyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.),and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.)were dissolved in anhydrous CH₂Cl₂ (25 mL). To this solution, a solutionof 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.)in anhydrous CH₂Cl₂ (25 mL) was added under N₂ and the reaction wasallowed to stir overnight at rt. Reaction mixture was concentrated invacuo and the resulting residue was dissolved in EtOAc, washed withwater (2×), NaHCO₃ (1×), water (1×), and brine (1×), dried over Na₂SO₄,filtered, and concentrated in vacuo, giving crude title compound, as abrown oil. The crude material was purified by chromatography on silicagel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex10%→20%→40%→70%], affording the title compound as a pale yellow solid.Additionally, the title compound could be prepared by the followingroute: 1,1′-Carbonyldiimidazole (CDT) (0.824 g, 5.08 mmol, 1.1 eq.) and3-methylenecyclobutanecarboxylic acid (0.570 g, 5.08 mmol, 1.1 eq.) weredissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g,4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9mmol, 3.0 eq.) in anhydrous CH₂Cl₂ (13 mL) was added to the acid mixtureand the reaction was allowed to stir at 60° C., under N₂, overnight. Thereaction mixture was concentrated in vacuo and the resulting residue wasdissolved in EtOAc, washed with NaHCO₃ (2×) and brine (1×), dried overNa₂SO₄, filtered, and concentrated in vacuo, giving crude titlecompound, as a brown oil. The crude material was purified bychromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge,eluting with EtOAc:Hex 10%→20%->40%→70%], affording the title compoundas a pale yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 2.86-2.96 (m, 2H),3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78(s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z238.19 (90) [MH⁺]; HPLC: t_(R)=2.67 min (OpenLynx, polar_(—)7 min).

C-(3-Chloropyrazin-2-yl)-methylamine bis-hydrochloride

A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0g, 36.5 mmol) in anhydrous CH₂Cl₂ (200 mL) was charged with hydrazine(2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N₂ atmosphere. After2.5 h, MeOH (300 mL) was added and the reaction was heated until thesolution was homogenous. The reaction mixture was allowed to stir for 19h. The white ppt which had formed (2,3-dihydrophthalazine-1,4-dionebyproduct), was filtered off and washed several times with ether. Theclear filtrate was concentrated in vacuo and the concentrate wasdissolved in EtOAc and filtered again to remove white ppt. All solventwas removed, giving a yellow oil which was dissolved into EtOAc andether and charged with HCl (g). The title compound, a pale yellow solid,instantly precipitated. The title compound was dried in a 40° C. ovenfor 72 h, affording the title compound, as a dark yellow solid; ¹H NMR(400 MHz, CD₃OD) δ 4.55 (2 H, s), 8.27 (1 H, d, J=2.52 Hz), 8.54 (1H, d,J=2.56 Hz); MS (ES+): m/z 143.96/145.96 (100/60) [MH⁺]; HPLC: t_(R)=0.41min (OpenLynx, polar_(—)7 min).

2-(3-Chloropyrazin-2-ylmethyl)-isoindole-1,3-dione

A solution of (3-chloropyrazin-2-yl)-methanol (47 g, 0.33 mol),isoindole-1,3-dione (58.3 g, 0.396 mol, 1.2 eq.), and triphenylphosphine(89.7 g, 0.396 mol, 1.2 eq.) in anhydrous THF (1.5 L) was charged withDIAD (80.2 g, 0.396 mol, 77.1 mL, 1.2 eq.) dropwise at rt, under N₂,making sure the internal temperature did not surpass 40° C. The crudematerial was adsorbed onto silica gel, dry loaded, and purified bychromatography on silica gel [6″X₁₆″ column, 2.75 kg silica gel, elutingwith Hex:CH₂Cl₂ 1:1→neat CH₂Cl₂→MeCN:CH₂Cl₂ 2→10%.] Material wascombined and concentrated in vacuo. Residue was dissolved as best aspossible in hot CH₂Cl₂ (500 mL), after which i-PrOH was added and awhite crystalline solid began to precipitate out of solution. Solid wasfiltered, washed with i-PrOH, and oven-dried to remove all traces ofsolvent, affording the title compound, as an off-white solid; ¹H NMR(400 MHz, CDCl₃) δ 5.10 (s, 1H), 7.75-7.80 (m, 2H), 7.89-7.94 (m, 2H),8.26 (1 H, d, J=2.45 Hz), 8.31 (1 H, d, J=2.49 Hz); MS (ES+): m/z274.21/276.19 (100/50) [MH⁺]; HPLC: t_(R) =3.35 min (OpenLynx,nonpolar_(—)7 min).

(3-Chloropyrazin-2-yl)-methanol

To a solution of 2,2,6,6-tetramethylpiperidine (TMP) (43.8 mL, 36.4 g,0.258 mol, 1.18 eq.) in anhydrous THF (600 mL), cooled to −78° C., 2.5 Mn-BuLi in hexanes (110.9 mL, 0.277 mol, 1.27 eq.) was added directly.The solution was allowed to warm to 0° C. for 20 min, after which thereaction was again cooled to −78° C. A solution of chloropyrazine (19.2mL, 25.0 g, 0.218 mol) in THF (50 mL) was added dropwise over 10 min; acolor change from light yellow to dark brown was observed. The reactionwas allowed to react at −78° C. to −70° C. for 10 min. A solution of DMF(42.0 mL, 39.9 g, 0.546 mol, 2.5 eq.) in THF (50 mL) was added slowlyover 12 min. The temperature was maintained at −78° C. to −70° C. for 2h. The reaction was quenched with MeOH (400 mL) at −78° C. and chargedwith NaBH₄ (16.5 g, 0.437 mol, 2.0 eq.) at 0° C. for 2 h. The solventwas partially removed in vacuo and additional CH₂Cl₂ (200 mL) was addedto the oil and the reaction mixture was quenched with 2N HCl (900 mL) toa neutral pH. The aqueous layer was extracted with CH₂Cl₂ (4×) and EtOAc(2×). The organic layers were combined, dried over Na₂SO₄, filtered, andconcentrated in vacuo, giving a crude black liquid. The crude materialwas adsorbed onto silica gel (for dry loading) and purified bychromatography on silica gel [2 kg silica gel, eluting with MeCN:CH₂Cl₂2%→5%→10%] affording the title compound, as a dark brown oil; ¹H NMR(400 MHz, CDCl₃) δ 4.86 (2 H, s), 8.36 (1 H, d, J=4.35 Hz), 8.51 (1 H,d, J=2.56 Hz); MS (ES+): m/z 144.93 (100) [MH⁺]; HPLC: t_(R)=1.60 min(OpenLynx, polar_(—)7 min).

1. A process for preparing a compound of Formula I comprising reacting acompound of formula I-AAA with Q¹-B(OR)₂ under suitable couplingconditions according to the following scheme:

wherein A¹¹ is Br or I; B(OR)₂ is a boronic acid or ester; Q¹ is

E^(11a) is H or CH₃; E^(11b) is H or F; R¹ is

 and G^(11a) and G^(11b) are each independently H, —CH₃, —OH, —CH₂OH,


2. The process of claim 1, wherein R¹ is


3. The process of claim 2, wherein E^(11a) and E^(11b) are both H. 4.The process of claim 3, wherein A¹¹ is Br.
 5. The process of claim 1,wherein the compound of formula I-AAA is prepared by treating a compoundof formula II-Z with ammonia


6. The process of claim 5, wherein A¹¹ is Br.
 7. The process of claim 6,wherein R¹ is:


8. The process of claim 7, wherein E^(11a) and E^(11b) are both H.